Skip to main content
Log in

Oral Anticancer Drugs: Mechanisms of Low Bioavailability and Strategies for Improvement

Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

The use of oral anticancer drugs has increased during the last decade, because of patient preference, lower costs, proven efficacy, lack of infusion-related inconveniences, and the opportunity to develop chronic treatment regimens. Oral administration of anticancer drugs is, however, often hampered by limited bioavailability of the drug, which is associated with a wide variability. Since most anticancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in the bioavailability can have a negative impact on treatment outcome. This review discusses mechanisms of low bioavailability of oral anticancer drugs and strategies for improvement. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug’s stability in the gastrointestinal tract, factors affecting dissolution, the rate of passage through the gut wall, and the pre-systemic metabolism in the gut wall and liver. These factors are divided into pharmaceutical limitations, physiological endogenous limitations, and patient-specific limitations. There are several strategies to reduce or overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form, or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. Although the bioavailability can be enhanced by various strategies, the development of novel oral products with low solubility or cell membrane permeability remains cumbersome and is often unsuccessful. The main reasons are unacceptable variation in the bioavailability and high investment costs. Furthermore, novel oral anticancer drugs are frequently associated with toxic effects including unacceptable gastrointestinal adverse effects. Therefore, compliance is often suboptimal, which may negatively influence treatment outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. O’Neill VJ, Twelves CJ. Oral cancer treatment: developments in chemotherapy and beyond. Br J Cancer. 2002;87(9):933–7.

    PubMed  Google Scholar 

  2. Liu G, Franssen E, Fitch MI, et al. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15(1):110–5.

    PubMed  CAS  Google Scholar 

  3. Bridges JFP, Mohamed AF, Finnern HW, et al. Patients’ preferences for treatment outcomes for advanced non-small cell lung cancer: a conjoint analysis. Lung Cancer. 2012;77(1):224–31.

    PubMed  Google Scholar 

  4. Benjamin L, Cotté F-E, Philippe C, et al. Physicians’ preferences for prescribing oral and intravenous anticancer drugs: a discrete choice experiment. Eur J Cancer. 2012;48(6):912–20.

    PubMed  Google Scholar 

  5. Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59(1):56–66.

    PubMed  Google Scholar 

  6. Mastroianni CM, Viscomi C, Ceniti S, et al. Preferences of patients with advanced colorectal cancer for treatment with oral or intravenous chemotherapy. Patient. 2008;1(3):181–7.

    PubMed  Google Scholar 

  7. Lima PR, del Giglio A. Randomized crossover trial of intravenous 5-FU versus oral UFT both modulated by leucovorin: a one-centre experience. Eur J Cancer Care (Engl). 2005;14(2):151–4.

    Google Scholar 

  8. Bonastre J, Jan P, Barthe Y, et al. Metastatic breast cancer: we do need primary cost data. Breast. 2012;21(3):384–8.

    PubMed  CAS  Google Scholar 

  9. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4(6):423–36.

    PubMed  CAS  Google Scholar 

  10. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666–76.

    PubMed  CAS  Google Scholar 

  11. Gelderblom H, Verweij J, Nooter K, Nooter K, et al. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37(13):1590–8.

    PubMed  CAS  Google Scholar 

  12. Bhatt RS, Merchan J, Parker R, et al. A phase 2 pilot trial of low-dose, continuous infusion, or “metronomic” paclitaxel and oral celecoxib in patients with metastatic melanoma. Cancer. 2010;116(7):1751–6.

    PubMed  CAS  Google Scholar 

  13. Hellriegel ET, Bjornsson TD, Hauck WW. Interpatient variability in bioavailability is related to the extent of absorption: implications for bioavailability and bioequivalence studies. Clin Pharmacol Ther. 1996;60(6):601–7.

    PubMed  CAS  Google Scholar 

  14. US Food and Drug Administration. Guidance for industry, bioavailability and bioequivalence studies for orally administered drug products—general considerations; 2003. http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070124.pdf. Accessed 14 Feb 2013

  15. US Food and Drug Administration. Code of Federal Regulations. Title 21: food and drugs. Part 320—bioavailability and bioequivalence studies. 320.21. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=320. Accessed 14 Feb 2013

  16. Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984;9(1):1–25.

    PubMed  CAS  Google Scholar 

  17. Burton PS, Goodwin JT, Vidmar TJ, et al. Predicting drug absorption: how nature made it a difficult problem. J Pharmacol Exp Ther. 2002;303(3):889–95.

    PubMed  CAS  Google Scholar 

  18. Noyes AS, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19:930–4.

    Google Scholar 

  19. Dressman JB, Amidon GL, Reppas C, et al. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res. 1998;15(1):11–22.

    PubMed  CAS  Google Scholar 

  20. Evans DF, Pye G, Bramley R, et al. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut. 1988;29(8):1035–41.

    PubMed  CAS  Google Scholar 

  21. Ewe K, Schwartz S, Petersen S, et al. Inflammation does not decrease intraluminal pH in chronic inflammatory bowel disease. Dig Dis Sci. 1999;44(7):1434–9.

    PubMed  CAS  Google Scholar 

  22. Press AG, Hauptmann IA, Hauptmann L, et al. Gastrointestinal pH profiles in patients with inflammatory bowel disease. Aliment pharmacol Ther. 1998;12(7):673–8.

    PubMed  CAS  Google Scholar 

  23. Washington N, Washington C, Wilson C. Small intestine: transit and absorption of drugs. In: Physiological pharmaceutics. London: Taylor & Francis; 1989. p. 71–90.

  24. European Medicines Agency. Iressa. Summary of product characteristics (SPC). http://www.medicines.org.uk/emc/medicine/22104/SPC/. Accessed 27 May 2012.

  25. European Medicines Agency. Tyverb. Summary of product characteristics (SPC). http://www.medicines.org.uk/emc/medicine/20929/SPC/tyverb/. Accessed 27 May 2012.

  26. Eley T, Luo FR, Agrawal S, et al. Phase I study of the effect of gastric acid pH modulators on the bioavailability of oral dasatinib in healthy subjects. J Clin Pharmacol. 2009;49(6):700–9.

    PubMed  CAS  Google Scholar 

  27. Joel SP, Clark PI, Slevin ML. Stability of the i.v. and oral formulations of etoposide in solution. Cancer Chemother Pharmacol. 1995;37(1–2):117–24.

    PubMed  CAS  Google Scholar 

  28. Joel SP, Clark PI, Heap L, et al. Pharmacological attempts to improve the bioavailability of oral etoposide. Cancer Chemother Pharmacol. 1995;37(1–2):125–33.

    PubMed  CAS  Google Scholar 

  29. Toffoli G, Corona G, Basso B, et al. Pharmacokinetic optimisation of treatment with oral etoposide. Clinical Pharmacokinet. 2004;43(7):441–66.

    CAS  Google Scholar 

  30. Adair CG, Bridges JM, Desai ZR. Can food affect the bioavailability of chlorambucil in patients with haematological malignancies? Cancer Chemother Pharmacol. 1986;17(1):99–102.

    PubMed  CAS  Google Scholar 

  31. Amidon GL, Lennernäs H, Shah VP, et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    PubMed  CAS  Google Scholar 

  32. Butler JM, Dressman JB. The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci. 2010;99(12):4940–54.

    PubMed  CAS  Google Scholar 

  33. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–49.

    PubMed  CAS  Google Scholar 

  34. van Hoogevest P, Liu X, Fahr A. Drug delivery strategies for poorly water-soluble drugs: the industrial perspective. Expert Opin Drug Deliv. 2011;8(11):1481–500.

    PubMed  Google Scholar 

  35. Yáñez JA, Wang SWJ, Knemeyer IW, et al. Intestinal lymphatic transport for drug delivery. Adv Drug Deliv Rev. 2011;63(10–11):923–42.

    PubMed  Google Scholar 

  36. Chan LMS, Lowes S, Hirst BH. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci. 2004;21(1):25–51.

    PubMed  CAS  Google Scholar 

  37. van Herwaarden AE, van Waterschoot RAB, Schinkel AH. How important is intestinal cytochrome P450 3A metabolism? Trends Pharmacol Sci. 2009;30(5):223–7.

    PubMed  Google Scholar 

  38. Natarajan K, Xie Y, Baer MR, Ross DD. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol. 2012;83(8):1084–103.

    PubMed  CAS  Google Scholar 

  39. Kuppens IELM, Breedveld P, Beijnen JH, et al. Modulation of oral drug bioavailability: from preclinical mechanism to therapeutic application. Cancer Invest. 2005;23(5):443–64.

    PubMed  CAS  Google Scholar 

  40. Bardelmeijer HA, Ouwehand M, Beijnen JH, et al. Efficacy of novel P-glycoprotein inhibitors to increase the oral uptake of paclitaxel in mice. Invest New Drugs. 2004;22(3):219–29.

    PubMed  CAS  Google Scholar 

  41. van Waterschoot RAB, Schinkel AH. A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice. Pharmacol Rev. 2011;63(2):390–410.

    PubMed  Google Scholar 

  42. Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev. 2003;55(1):3–29.

    PubMed  CAS  Google Scholar 

  43. Ni L-N, Li J-Y, Miao K-R, et al. Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol. 2011;28(1):265–9.

    PubMed  CAS  Google Scholar 

  44. Dohse M, Scharenberg C, Shukla S, et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos. 2010;38(8):1371–80.

    PubMed  CAS  Google Scholar 

  45. Bansal T, Mishra G, Jaggi M, et al. Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats. Eur J Pharm Sci. 2009;36(4–5):580–90.

    PubMed  CAS  Google Scholar 

  46. Bardelmeijer HA, Ouwehand M, Buckle T, et al. Low systemic exposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by ritonavir. Cancer Res. 2002;62(21):6158–64.

    PubMed  CAS  Google Scholar 

  47. Lacayo NJ, Duran GE, Sikic BI. Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells. J Exp Ther Oncol. 2003;3(3):127–35.

    PubMed  CAS  Google Scholar 

  48. Banna GL, Collovà E, Gebbia V, et al. Anticancer oral therapy: emerging related issues. Cancer Treat Rev. 2010;36(8):595–605.

    PubMed  Google Scholar 

  49. Lagas JS, Fan L, Wagenaar E, et al. P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 determine the pharmacokinetics of etoposide. Clin Cancer Res. 2010;16(1):130–40.

    PubMed  CAS  Google Scholar 

  50. Suzuki H, Sugiyama Y. Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition. Adv Drug Deliv Rev. 2002;54(10):1311–31.

    PubMed  CAS  Google Scholar 

  51. Huisman MT, Chhatta A, van Tellingen O, et al. MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer. 2005;116(5):824–9.

    PubMed  CAS  Google Scholar 

  52. Lai L, Tan TMC. Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues. Biochem J. 2002;361(Pt 3):497–503.

    PubMed  CAS  Google Scholar 

  53. Wittgen HGM, van den Heuvel JJMW, Krieger E, et al. Phenylalanine 368 of multidrug resistance-associated protein 4 (MRP4/ABCC4) plays a crucial role in substrate-specific transport activity. Biochem Pharmacol. 2012;84(3):366–73.

    PubMed  CAS  Google Scholar 

  54. Maliepaard M, Scheffer GL, Faneyte IF, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 2001;61(8):3458–64.

    PubMed  CAS  Google Scholar 

  55. Fetsch P, Abati A, Litman T, et al. Localization of the ABCG2 mitoxantrone resistance-associated protein in normal tissues. Cancer Lett. 2006;235(1):84–92.

    PubMed  CAS  Google Scholar 

  56. Dankers AC, Sweep FCGJ, Pertijs JCLM, et al. Localization of breast cancer resistance protein (Bcrp) in endocrine organs and inhibition of its transport activity by steroid hormones. Cell Tissue Res. 2012;349(2):551–63.

    PubMed  CAS  Google Scholar 

  57. Anger GJ, Cressman AM, Piquette-Miller M. Expression of ABC Efflux transporters in placenta from women with insulin-managed diabetes. PloS ONE. 2012;7(4):e35027.

    PubMed  CAS  Google Scholar 

  58. Allen JD, Brinkhuis RF, Wijnholds J, et al. The mouse Bcrp1/Mxr/Abcp gene: amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res. 1999;59(17):4237–41.

    PubMed  CAS  Google Scholar 

  59. Vlaming MLH, van Esch A, van de Steeg E, et al. Impact of abcc2 [multidrug resistance-associated protein (MRP) 2], abcc3 (MRP3), and abcg2 (breast cancer resistance protein) on the oral pharmacokinetics of methotrexate and its main metabolite 7-hydroxymethotrexate. Drug Metab Dispos. 2011;39(8):1338–44.

    PubMed  CAS  Google Scholar 

  60. Marchetti S, de Vries N, Buckle T, et al. Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008;7(8):2280–7.

    PubMed  CAS  Google Scholar 

  61. Balabanov S, Gontarewicz A, Keller G, et al. Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor danusertib in BCR-ABL-positive cells in vitro. PloS ONE. 2011;6(4):e19164.

    PubMed  CAS  Google Scholar 

  62. Polli JW, Humphreys JE, Harmon KA, et al. The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos. 2008;36(4):695–701.

    PubMed  CAS  Google Scholar 

  63. Chen Y-J, Huang W-C, Wei Y-L, et al. Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells. PloS ONE. 2011;6(6):e21428.

    PubMed  CAS  Google Scholar 

  64. Seamon JA, Rugg CA, Emanuel S, et al. Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor. Mol Cancer Ther. 2006;5(10):2459–67.

    PubMed  CAS  Google Scholar 

  65. Masuda S, Uemoto S, Hashida T, et al. Effect of intestinal P-glycoprotein on daily tacrolimus trough level in a living-donor small bowel recipient. Clin Pharmacol Ther. 2000;68(1):98–103.

    PubMed  CAS  Google Scholar 

  66. Vasconcelos FC, Silva KL, Souza PSD, et al. Variation of MDR proteins expression and activity levels according to clinical status and evolution of CML patients. Cytometry B Clin Cytom. 2011;80(3):158–66.

    PubMed  Google Scholar 

  67. Deenen MJ, Cats A, Beijnen JH, et al. Part 2: pharmacogenetic variability in drug transport and phase I anticancer drug metabolism. Oncologist. 2011;16(6):820–34.

    PubMed  CAS  Google Scholar 

  68. Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol. 1999;39:1–17.

    PubMed  CAS  Google Scholar 

  69. Benet LZ, Cummins CL. The drug efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev. 2001;50(Suppl 1):S3–11.

    PubMed  CAS  Google Scholar 

  70. Lamba JK, Lin YS, Schuetz EG, et al. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2002;54(10):1271–94.

    PubMed  CAS  Google Scholar 

  71. Gorski JC, Vannaprasaht S, Hamman M, et al. The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity. Clin Pharmacol Ther. 2003;74(3):275–87.

    PubMed  CAS  Google Scholar 

  72. von Richter O, Burk O, Fromm MF, et al. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2004;75(3):172–83.

    Google Scholar 

  73. Huang S-M, Strong JM, Zhang L, et al. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J Clin Oncol. 2008;48(6):662–70.

    CAS  Google Scholar 

  74. Mandlekar S, Hong J-L, Kong A-NT. Modulation of metabolic enzymes by dietary phytochemicals: a review of mechanisms underlying beneficial versus unfavorable effects. Curr Drug Metab. 2006;7(6):661–75.

    PubMed  CAS  Google Scholar 

  75. Baker SD, Khor SP, Adjei AA, et al. Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Oncol. 1996;14(12):3085–96.

    PubMed  CAS  Google Scholar 

  76. Spector T, Harrington JA, Porter DJ. 5-Ethynyluracil (776C85): inactivation of dihydropyrimidine dehydrogenase in vivo. Biochem Pharmacol. 1993;46(12):2243–8.

    PubMed  CAS  Google Scholar 

  77. Koolen SLW, Witteveen PO, Jansen RS, et al. Phase I study of oral gemcitabine prodrug (LY2334737) alone and in combination with erlotinib in patients with advanced solid tumors. Clin Cancer Res. 2011;17(18):6071–82.

    PubMed  CAS  Google Scholar 

  78. Christophidis N, Vajda FJ, Lucas I, et al. Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration. Clin Pharmacokinet. 1978;3(4):330–6.

    Google Scholar 

  79. Schöffski P. The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors. Anticancer Drugs. 2004;15(2):85–106.

    PubMed  Google Scholar 

  80. Harvey VJ, Slevin ML, Joel SP, et al. The effect of dose on the bioavailability of oral etoposide. Cancer Chemother Pharmacol. 1986;16(2):178–81.

    PubMed  CAS  Google Scholar 

  81. Hande KR, Krozely MG, Greco F, et al. Bioavailability of low-dose oral etoposide. J Clin Oncol. 1993;11(2):374–7.

    PubMed  CAS  Google Scholar 

  82. Chabot GG, Armand JP, Terret C, et al. Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study. J Clin Oncol. 1996;14(7):2020–30.

    PubMed  CAS  Google Scholar 

  83. Sharma S. Patient selection for oral chemotherapy. Oncology (Williston Park). 2001;15(1 Suppl 2):33–5.

    CAS  Google Scholar 

  84. Dias VC, Madsen KL, Mulder KE, et al. Oral administration of rapamycin and cyclosporine differentially alter intestinal function in rabbits. Dig Dis Sci. 1998;43(10):2227–36.

    PubMed  CAS  Google Scholar 

  85. Eklund JW, Trifilio S, Mulcahy MF. Chemotherapy dosing in the setting of liver dysfunction. Oncology (Williston Park). 2005;19(8):1057–69.

    Google Scholar 

  86. Lorusso PM, Venkatakrishnan K, Ramanathan RK, et al. Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432. Clin Cancer Res. 2012;18(10):2954–63.

    PubMed  CAS  Google Scholar 

  87. US Food and Drug Administration. Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. Guidance for industry 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf. Accessed 14 Feb 2013

  88. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharm Res. 2004;56(2):163–84.

    CAS  Google Scholar 

  89. Malaguarnera G, Leggio F, Vacante M, et al. Probiotics in the gastrointestinal diseases of the elderly. J Nutr Health Aging. 2012;16(4):402–10.

    PubMed  CAS  Google Scholar 

  90. Grassi M, Petraccia L, Mennuni G, et al. Changes, functional disorders, and diseases in the gastrointestinal tract of elderly. Nutr Hosp. 2011;26(4):659–68.

    PubMed  CAS  Google Scholar 

  91. Schmucker DL. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging. 2001;18(11):837–51.

    PubMed  CAS  Google Scholar 

  92. Ling J, Fettner S, Lum BL, et al. Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals. Anticancer Drugs. 2008;19(2):209–16.

    PubMed  CAS  Google Scholar 

  93. Koch KM, Reddy NJ, Cohen RB, et al. Effects of food on the relative bioavailability of lapatinib in cancer patients. J Clin Oncol. 2009;27(8):1191–6.

    PubMed  CAS  Google Scholar 

  94. Martin P, Oliver S, Kennedy S-J, et al. Pharmacokinetics of vandetanib: three phase I studies in healthy subjects. Clin Ther. 2012;34(1):221–37.

    PubMed  CAS  Google Scholar 

  95. Bello CL, Sherman L, Zhou J, et al. Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs. 2006;17(3):353–8.

    PubMed  CAS  Google Scholar 

  96. Singh BN, Malhotra BK. Effects of food on the clinical pharmacokinetics of anticancer agents: underlying mechanisms and implications for oral chemotherapy. Clin Pharmacokinet. 2004;43(15):1127–56.

    PubMed  CAS  Google Scholar 

  97. Bosch TM, Huitema ADR, Doodeman VD, et al. Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res. 2006;12(19):5786–93.

    PubMed  CAS  Google Scholar 

  98. Baker SD, Verweij J, Cusatis GA, et al. Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther. 2009;85(2):155–63.

    PubMed  CAS  Google Scholar 

  99. Deenen MJ, Cats A, Beijnen JH, et al. Part 1: background, methodology, and clinical adoption of pharmacogenetics. Oncologist. 2011;16(6):811–9.

    PubMed  CAS  Google Scholar 

  100. Deenen MJ, Cats A, Beijnen JH, et al. Part 3: pharmacogenetic variability in phase II anticancer drug metabolism. Oncologist. 2011;16(7):992–1005.

    PubMed  CAS  Google Scholar 

  101. Deenen MJ, Cats A, Beijnen JH, et al. Part 4: pharmacogenetic variability in anticancer pharmacodynamic drug effects. Oncologist. 2011;16(7):1006–20.

    PubMed  CAS  Google Scholar 

  102. Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60(9):1281–302.

    PubMed  CAS  Google Scholar 

  103. Savolainen M, Kogermann K, Heinz A, et al. Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy. Eur J Pharm Biopharm. 2009;71(1):71–9.

    PubMed  CAS  Google Scholar 

  104. Janssens S, Van den Mooter G. Review: physical chemistry of solid dispersions. J Pharm Pharmacol. 2009;61(12):1571–86.

    PubMed  CAS  Google Scholar 

  105. Thakral NK, Ray AR, Bar-Shalom D, et al. Soluplus-solubilized citrated camptothecin–a potential drug delivery strategy in colon cancer. AAPS PharmSciTech. 2012;13(1):59–66.

    PubMed  CAS  Google Scholar 

  106. Chen C, Huang X, Cai H, et al. Anti-proliferation and anti-angiogenesis of curcumin-K30 solid dispersion. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010;35(10):1029–36.

    PubMed  CAS  Google Scholar 

  107. Moes JJ, Koolen SLW, Huitema DR, et al. Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001). Int J Pharm. 2011;420(2):244–50.

    PubMed  CAS  Google Scholar 

  108. Marchetti S, Stuurman F, Koolen S, et al. Phase I study of weekly oral docetaxel (ModraDoc001) plus ritonavir in patients with advanced solid tumors. J Clin Oncol. 2012;30 (suppl; abstr 2550).

  109. Liu X, Sun J, Chen X, et al. Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion. J Pharm Pharmacol. 2012;64(6):775–82.

    PubMed  CAS  Google Scholar 

  110. Lush RM, McCune JS, Tetteh L, et al. The absolute bioavailability of oral vinorelbine in patients with solid tumors. Cancer Chemother Pharmacol. 2005;56(6):578–84.

    PubMed  CAS  Google Scholar 

  111. Rowinsky EK, Noe DA, Trump DL, et al. Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors. J Clin Oncol. 1994;12(9):1754–63.

    PubMed  CAS  Google Scholar 

  112. Zhou XJ, Boré P, Monjanel S, et al. Pharmacokinetics of navelbine after oral administration in cancer patients. Cancer Chemother Pharmacol. 1991;29(1):66–70.

    PubMed  CAS  Google Scholar 

  113. Zhou XJ, Zhou-Pan XR, Favre R, et al. Relative bioavailability of two oral formulations of navelbine in cancer patients. Biopharm Drug Dispos. 1994;15(7):577–86.

    PubMed  CAS  Google Scholar 

  114. Bourgeois H, Vermorken J, Dark G, et al. Evaluation of oral versus intravenous dose of vinorelbine to achieve equivalent blood exposures in patients with solid tumours. Cancer Chemother Pharmacol. 2007;60(3):407–13.

    PubMed  CAS  Google Scholar 

  115. Eckardt JR, von Pawel J, Pujol J-L, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol. 2007;25(15):2086–92.

    PubMed  CAS  Google Scholar 

  116. von Pawel J, Gatzemeier U, Pujol JL, et al. Phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol. 2001;19(6):1743–9.

    Google Scholar 

  117. Witterland AH, Koks CH, Beijnen JH. Etoposide phosphate, the water soluble prodrug of etoposide. Pharm World Sci. 1996;18(5):163–70.

    PubMed  CAS  Google Scholar 

  118. Hong YS, Kim K-P, Lim H-S, et al. A phase I study of DHP107, a mucoadhesive lipid form of oral paclitaxel, in patients with advanced solid tumors: Crossover comparisons with intravenous paclitaxel. Invest New Drugs. Epub 2012 Jun 14.

  119. Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006;29(3–4):278–87.

    PubMed  CAS  Google Scholar 

  120. Sachan R, Khatri K, Kasture SB. Self-emulsifying drug delivery system a novel approach for enhancement of bioavailability. Int J Pharm Tech Res. 2010;2(3):1738–45.

    CAS  Google Scholar 

  121. Gibaud S, Attivi D. Microemulsions for oral administration and their therapeutic applications. Expert Opin Drug Deliv. 2012;9(8):937–51.

    PubMed  CAS  Google Scholar 

  122. Yang S, Gursoy RN, Lambert G, et al. Enhanced oral absorption of paclitaxel in a novel self-microemulsifying drug delivery system with or without concomitant use of P-glycoprotein inhibitors. Pharm Res. 2004;21(2):261–70.

    PubMed  CAS  Google Scholar 

  123. Oostendorp RL, Buckle T, Lambert G, et al. Paclitaxel in self-micro emulsifying formulations: oral bioavailability study in mice. Invest New Drugs. 2010;29:768–76.

    Google Scholar 

  124. Chaurasiya A, Singh AK, Jain GK, et al. Dual approach utilizing self microemulsifying technique and novel P-gp inhibitor for effective delivery of taxanes. J Microencapsul. 2012;4:1–13.

    Google Scholar 

  125. Attivi D, Ajana I, Astier A, et al. Development of microemulsion of mitotane for improvement of oral bioavailability. Drug Dev Ind Pharm. 2010;36(4):421–7.

    PubMed  CAS  Google Scholar 

  126. Lu J-L, Wang J-C, Zhao S-X, et al. Self-microemulsifying drug delivery system (SMEDDS) improves anticancer effect of oral 9-nitrocamptothecin on human cancer xenografts in nude mice. Eur J Pharm Biopharm. 2008;69(3):899–907.

    PubMed  CAS  Google Scholar 

  127. Aamdal S, Awada A, Evans J, et al. First-in-man study of a novel nucleoside analogue, CP-4126, in patients with advanced solid tumours [abstract no. 496P]. Ann Oncol. 2008; 19(suppl 8):viii153–65. doi:10.1093/annonc/mdn508.

  128. Bergman AM, Adema AD, Balzarini J, et al. Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models. Invest New Drugs. 2011;29(3):456–66.

    PubMed  CAS  Google Scholar 

  129. Gao P, Rush BD, Pfund WP, et al. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J Pharm Sci. 2003;92(12):2386–98.

    PubMed  CAS  Google Scholar 

  130. Fenyvesi F, Kiss T, Fenyvesi E, et al. Randomly methylated β-cyclodextrin derivatives enhance taxol permeability through human intestinal epithelial Caco-2 cell monolayer. J Pharm Sci. 2011;100(11):4734–44.

    PubMed  CAS  Google Scholar 

  131. Agüeros M, Zabaleta V, Espuelas S, et al. Increased oral bioavailability of paclitaxel by its encapsulation through complex formation with cyclodextrins in poly(anhydride) nanoparticles. J Control Release. 2010;145(1):2–8.

    PubMed  Google Scholar 

  132. Lim J, Simanek EE. Triazine dendrimers as drug delivery systems: From synthesis to therapy. Adv Drug Deliv Rev. 2012;64(9):826–35.

    PubMed  CAS  Google Scholar 

  133. Kolhatkar RB, Swaan P, Ghandehari H. Potential oral delivery of 7-ethyl-10-hydroxy-camptothecin (SN-38) using poly(amidoamine) dendrimers. Pharm Res. 2008;25(7):1723–9.

    PubMed  CAS  Google Scholar 

  134. Dahmani FZ, Yang H, Zhou J, et al. Enhanced oral bioavailability of paclitaxel in pluronic/LHR mixed polymeric micelles: preparation, in vitro and in vivo evaluation. Eur J Pharm Sci. 2012;47(1):179–89.

    PubMed  CAS  Google Scholar 

  135. Nekkanti V, Venkateswarlu V, Ansari KA, et al. Development and pharmacological evaluation of a PEG based nanoparticulate camptothecin analog for oral administration. Curr Drug Deliv. 2011;8(6):661–6.

    PubMed  CAS  Google Scholar 

  136. Wang X, Fan J, Liu Y, et al. Bioavailability and pharmacokinetics of sorafenib suspension, nanoparticles and nanomatrix for oral administration to rat. Int J Pharm. 2011;419(1–2):339–46.

    PubMed  CAS  Google Scholar 

  137. Jonker JW, Smit JW, Brinkhuis RF, et al. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000;92(20):1651–6.

    PubMed  CAS  Google Scholar 

  138. Sparreboom A, Van Asperen J, Mayer U, et al. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A. 1997;94(5):2031–5.

    PubMed  CAS  Google Scholar 

  139. Van Asperen J, Van Tellingen O, Sparreboom A, et al. Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. Br J Cancer. 1997;76(9):1181–3.

    PubMed  Google Scholar 

  140. Van Asperen J, Van Tellingen O, Van der Valk M, et al. Enhanced oral absorption and decreased elimination of paclitaxel in mice cotreated with cyclosporin A. Clin Cancer Res. 1998;4(10):2293–7.

    PubMed  Google Scholar 

  141. Rottenberg S, Nygren AOH, Pajic M, et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci U S A. 2007;104(29):12117–22.

    PubMed  CAS  Google Scholar 

  142. Summers MA, Moore JL, McAuley JW. Use of verapamil as a potential P-glycoprotein inhibitor in a patient with refractory epilepsy. Ann Pharmacother. 2004;38(10):1631–4.

    PubMed  Google Scholar 

  143. Malingré MM, Schellens JH, Van Tellingen O, et al. Metabolism and excretion of paclitaxel after oral administration in combination with cyclosporin A and after i.v. administration. Anticancer Drugs. 2000;11(10):813–20.

    PubMed  Google Scholar 

  144. Maliepaard M, Van Gastelen MA, Tohgo A, et al. Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res. 2001;7(4):935–41.

    PubMed  CAS  Google Scholar 

  145. Shonukan O, Dantzig AH, Kloeker-Rhoades S, et al. Development of LY2334737, an oral gemcitabine prodrug for continuous administration. Perspectives for the therapy of mature T-cell and NK-cell lymphomas. Hematol Meet Rep. 2009;3(1):69.

    Google Scholar 

  146. Chi KN, Chia SK, Dixon R, et al. A phase I pharmacokinetic study of the P-glycoprotein inhibitor, ONT-093, in combination with paclitaxel in patients with advanced cancer. Invest New Drugs. 2005;23(4):311–5.

    PubMed  CAS  Google Scholar 

  147. Kelly RJ, Draper D, Chen CC, et al. A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin Cancer Res. 2011;17(3):569–80.

    PubMed  CAS  Google Scholar 

  148. Joo KM, Song SY, Park K, et al. Response of brain specific microenvironment to P-glycoprotein inhibitor: an important factor determining therapeutic effect of P-glycoprotein inhibitor on brain metastatic tumors. Int J Oncol. 2008;33(4):705–12.

    PubMed  CAS  Google Scholar 

  149. Kelly RJ, Robey RW, Chen CC, et al. A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors. Oncologist. 2012;17(4):512.

    PubMed  Google Scholar 

  150. Jin J, Bi H, Hu J, et al. Enhancement of oral bioavailability of paclitaxel after oral administration of Schisandrol B in rats. Biopharm Drug Dispos. 2010;31(4):264–8.

    PubMed  CAS  Google Scholar 

  151. Gu X, Ren Z, Tang X, et al. Synthesis and biological evaluation of bifendate-chalcone hybrids as a new class of potential P-glycoprotein inhibitors. Bioorg Med Chem. 2012;20(8):2540–8.

    PubMed  CAS  Google Scholar 

  152. Wesołowska O. Interaction of phenothiazines, stilbenes and flavonoids with multidrug resistance-associated transporters, P-glycoprotein and MRP1. Acta Biochim Pol. 2011;58(4):433–48.

    PubMed  Google Scholar 

  153. Yokooji T, Murakami T, Yumoto R, et al. Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats. J Pharm Pharmacol. 2007;59(9):1263–70.

    PubMed  CAS  Google Scholar 

  154. González-Lobato L, Real R, Prieto JG, et al. Differential inhibition of murine Bcrp1/Abcg2 and human BCRP/ABCG2 by the mycotoxin fumitremorgin C. Eur J Pharmacol. 2010;644(1–3):41–8.

    PubMed  Google Scholar 

  155. Barrera B, Otero JA, Egido E, et al. The anthelmintic triclabendazole and its metabolites inhibit the membrane transporter ABCG2/BCRP. Antimicrob Agents Chemother. 2012;56(7):3535–43.

    PubMed  CAS  Google Scholar 

  156. Pick A, Müller H, Mayer R, et al. Structure-activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP). Bioorg Med Chem. 2011;19(6):2090–102.

    PubMed  CAS  Google Scholar 

  157. Gupta A, Unadkat JD, Mao Q. Interactions of azole antifungal agents with the human breast cancer resistance protein (BCRP). J Pharm Sci. 2007;96(12):3226–35.

    PubMed  CAS  Google Scholar 

  158. Helgason HH, Kruijtzer CMF, Huitema ADR, et al. Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer. Br J Cancer. 2006;95(7):794–800.

    PubMed  CAS  Google Scholar 

  159. Kruijtzer CMF, Boot H, Beijnen JH, et al. Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer. Ann Oncol. 2003;14(2):197–204.

    PubMed  CAS  Google Scholar 

  160. Kruijtzer CMF, Schellens JHM, Mezger J, et al. Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2002;20(23):4508–16.

    PubMed  CAS  Google Scholar 

  161. Oostendorp RL, Huitema A, Rosing H, et al. Coadministration of ritonavir strongly enhances the apparent oral bioavailability of docetaxel in patients with solid tumors. Clin Cancer Res. 2009;15(12):4228–33.

    PubMed  CAS  Google Scholar 

  162. Santos JR, Moltó J, Llibre JM, et al. Antiretroviral simplification with darunavir/ritonavir monotherapy in routine clinical practice: safety, effectiveness, and impact on lipid profile. PloS ONE. 2012;7(5):e37442.

    PubMed  CAS  Google Scholar 

  163. Bánhegyi D, Katlama C, Da Cunha CA, et al. Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN. Curr HIV Res. 2012. Epub 2012 Feb 2.

  164. Blick G, Greiger-Zanlungo P, Gretz S, et al. Long-term efficacy and safety of once-daily fosamprenavir 1400 mg boosted by ritonavir 100 mg: the BOLD100 study. Int J STD AIDS. 2012;23(3):e18–22.

    PubMed  CAS  Google Scholar 

  165. Baccanari DP, Davis ST, Knick VC, et al. 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci U S A. 1993;90(23):11064–8.

    PubMed  CAS  Google Scholar 

  166. Takechi T, Fujioka A, Matsushima E, et al. Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells. Eur J Cancer. 2002;38(9):1271–7.

    PubMed  CAS  Google Scholar 

  167. Anttila MI, Sotaniemi EA, Kairaluoma MI, et al. Pharmacokinetics of ftorafur after intravenous and oral administration. Cancer Chemother Pharmacol. 1983;10(3):150–3.

    PubMed  CAS  Google Scholar 

  168. Yamashita K, Yada H, Ariyoshi T. Neurotoxic effects of alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA) on dogs. J Toxicol Sci. 2004;29(2):155–66.

    PubMed  CAS  Google Scholar 

  169. Shirasaka T, Shimamoto Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res. 1993;53(17):4004–9.

    PubMed  CAS  Google Scholar 

  170. Schilsky RL, Levin J, West WH, et al. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002;20(6):1519–26.

    PubMed  CAS  Google Scholar 

  171. Spector T, Cao S. A possible cause and remedy for the clinical failure of 5-fluorouracil plus eniluracil. Clin Colorectal Cancer. 2010;9(1):52–4.

    PubMed  CAS  Google Scholar 

  172. Kobayakawa M, Kojima Y. Tegafur/gimeracil/oteracil (S-1) approved for the treatment of advanced gastric cancer in adults when given in combination with cisplatin: a review comparing it with other fluoropyrimidine-based therapies. Onco Targets Ther. 2011;4:193–201.

    PubMed  CAS  Google Scholar 

  173. MerckSerono. UFT® (tegafur-uracil) oral 5-FU therapy. http://www.merckserono.com/en/products/oncology/colorectal_cancer/uft/uft.html. Accessed 9 Jun 2012.

  174. Alani AWG, Rao DA, Seidel R, et al. The effect of novel surfactants and Solutol HS 15 on paclitaxel aqueous solubility and permeability across a Caco-2 monolayer. J Pharm Sci. 2010;99(8):3473–85.

    PubMed  CAS  Google Scholar 

  175. Loftsson T, Duchêne D. Cyclodextrins and their pharmaceutical applications. Int J Pharm. 2007;329(1–2):1–11.

    PubMed  CAS  Google Scholar 

  176. Fenyvesi F, Fenyvesi E, Szente L, et al. P-glycoprotein inhibition by membrane cholesterol modulation. Eur J Pharm Sci. 2008;34(4–5):236–42.

    PubMed  CAS  Google Scholar 

  177. Zhang Y, Wang Q-S, Cui Y-L, et al. Changes in the intestinal absorption mechanism of icariin in the nanocavities of cyclodextrins. Int J Nanomed. 2012;7:4239–49.

    CAS  Google Scholar 

  178. Ishikawa M, Yoshii H, Furuta T. Interaction of modified cyclodextrins with cytochrome P-450. Biosci Biotechnol Biochem. 2005;69(1):246–8.

    PubMed  CAS  Google Scholar 

  179. Marigny K, Aubin F, Burgot G, et al. Particular cutaneous side effects with etoposide-containing courses: is VP16 or etoposide phosphate responsible? Cancer Chemother Pharmacol. 2005;55(3):244–50.

    PubMed  CAS  Google Scholar 

  180. De Jong RS, Slijfer EA, Uges DR, et al. Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile. Br J Cancer. 1997;76(11):1480–3.

    PubMed  Google Scholar 

  181. De Jong RS, Mulder NH, Uges DR, et al. Randomized comparison of etoposide pharmacokinetics after oral etoposide phosphate and oral etoposide. Br J Cancer. 1997;75(11):1660–6.

    PubMed  Google Scholar 

  182. Kim HK, Lin CC, Parker D, et al. High-performance liquid chromatographic determination and stability of 5-(3-methyltriazen-1-yl)-imidazo-4-carboximide, the biologically active product of the antitumor agent temozolomide, in human plasma. J Chromatogr B Biomed Sci Appl. 1997;703(1–2):225–33.

    PubMed  CAS  Google Scholar 

  183. Tsang LL, Quarterman CP, Gescher A, et al. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. Cancer Chemother Pharmacol. 1991;27(5):342–6.

    PubMed  CAS  Google Scholar 

  184. Diez BD, Statkevich P, Zhu Y, et al. Evaluation of the exposure equivalence of oral versus intravenous temozolomide. Cancer Chemother Pharmacol. 2010;65(4):727–34.

    PubMed  CAS  Google Scholar 

  185. Marzolini C, Decosterd LA, Shen F, et al. Pharmacokinetics of temozolomide in association with fotemustine in malignant melanoma and malignant glioma patients: comparison of oral, intravenous, and hepatic intra-arterial administration. Cancer Chemother Pharmacol. 1998;42(6):433–40.

    PubMed  CAS  Google Scholar 

  186. European Medicines Agency. Assessment report for temozolomide. EMA/51724/2010. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001124/WC500073303.pdf. Accessed 29 Jan 2013.

  187. Schellens JHM. Capecitabine. Oncologist. 2007;12(2):152–5.

    PubMed  CAS  Google Scholar 

  188. Twelves C, Glynne-Jones R, Cassidy J, et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res. 1999;5(7):1696–702.

    PubMed  CAS  Google Scholar 

  189. Van Der Heyden SA, Highley MS, De Bruijn E, et al. Pharmacokinetics and bioavailability of oral 5′-deoxy-5-fluorouridine in cancer patients. Br J Cancer. 1999;47(4):351–6.

    Google Scholar 

  190. Ochoa L, Hurwitz HI, Wilding G, et al. Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies. Ann Oncol. 2000;11(10):1313–22.

    PubMed  CAS  Google Scholar 

  191. Nemunaitis J, Eager R, Twaddell T, et al. Phase I assessment of the pharmacokinetics, metabolism, and safety of emitefur in patients with refractory solid tumors. J Clin Oncol. 2000;18(19):3423–34.

    PubMed  CAS  Google Scholar 

  192. Hofheinz R-D, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012;13(6):579–88.

    PubMed  CAS  Google Scholar 

  193. Koukourakis GV, Zacharias G, Tsalafoutas J, et al. Capecitabine for locally advanced and metastatic colorectal cancer: a review. World J Gastrointest Oncol. 2010;2(8):311–21.

    PubMed  Google Scholar 

  194. Shipley LA, Brown TJ, Cornpropst JD, et al. Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs. Drug Metab Dispos. 2006;20(6):849–55.

    Google Scholar 

  195. Plunkett W, Huang P, Searcy CE, et al. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol. 1996;23(5 Suppl 10):3–15.

    PubMed  CAS  Google Scholar 

  196. Veltkamp SA, Jansen RS, Callies S, et al. Oral administration of gemcitabine in patients with refractory tumors: a clinical and pharmacologic study. Clin Cancer Res. 2008;14(11):3477–86.

    PubMed  CAS  Google Scholar 

  197. Bender DM, Bao J, Dantzig AH, et al. Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine. J Med Chem. 2009;52(22):6958–61.

    PubMed  CAS  Google Scholar 

  198. Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol. 1991;9(3):491–8.

    PubMed  CAS  Google Scholar 

  199. Stuurman FE, Voest EE, Awada A, et al. Phase I study of oral CP-4126, a gemcitabine analog, in patients with advanced solid tumours. Eur J Cancer Supp. 2010;8(7):135.

    Google Scholar 

  200. Berlin J, Benson AB, Ruben P, et al. Phase I safety, pharmacokinetic (PK), and bioavailability (F) study of a semi-solid matrix (SSM) formulation of oral irinotecan in patients with advanced solid tumors. J Clin Oncol (Meeting Abstracts). 2003;22(abstr 521).

  201. Bansal T, Awasthi A, Jaggi M, et al. Pre-clinical evidence for altered absorption and biliary excretion of irinotecan (CPT-11) in combination with quercetin: possible contribution of P-glycoprotein. Life Sci. 2008;83(7–8):250–9.

    PubMed  CAS  Google Scholar 

  202. Haaz MC, Rivory L, Riché C, et al. Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. Cancer Res. 1998;58(3):468–72.

    PubMed  CAS  Google Scholar 

  203. Pommier Y, Topoisomerase I. Inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006;6(10):789–802.

    PubMed  CAS  Google Scholar 

  204. Furman WL, Navid F, Daw NC, et al. Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors. J Clin Oncol. 2009;27(27):4599–604.

    PubMed  CAS  Google Scholar 

  205. Aszalos A. Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) II. Clinical aspects. Drug Discov Today. 2007;12(19–20):838–43.

    PubMed  CAS  Google Scholar 

  206. European Medicines Agency/Committee for Medicinal Products for Human Use (CHMP) Think-Tank Group on Innovative Drug Development. Medicines and emerging science. http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000339.jsp&mid=WC0b01ac05800baed8. Accessed 10 Jun 2012.

  207. Findlay M, Von Minckwitz G, Wardley A. Effective oral chemotherapy for breast cancer: pillars of strength. Ann Oncol. 2008;19(2):212–22.

    PubMed  CAS  Google Scholar 

  208. Foulon V, Schöffski P, Wolter P. Patient adherence to oral anticancer drugs: an emerging issue in modern oncology. Acta Clin Belg. 2011;66(2):85–96.

    PubMed  CAS  Google Scholar 

  209. Loriot Y, Perlemuter G, Malka D, et al. Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy. Nat Clin Pract Oncol. 2008;5(5):268–78.

    PubMed  CAS  Google Scholar 

  210. Peterson PN, Shetterly SM, Clarke CL, et al. Health literacy and outcomes among patients with heart failure. JAMA. 2011;305(16):1695–701.

    PubMed  CAS  Google Scholar 

  211. Klümpen H-J, Samer CF, Mathijssen RHJ, et al. Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treat Rev. 2011;37(4):251–60.

    PubMed  Google Scholar 

  212. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005;23(24):5474–83.

    PubMed  CAS  Google Scholar 

  213. Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol. 2004;22(5):935–42.

    PubMed  CAS  Google Scholar 

  214. Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol. 2002;20(9):2240–50.

    PubMed  CAS  Google Scholar 

  215. Meerum Terwogt JM, Malingré MM, Beijnen JH, et al. Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res. 1999;5(11):3379–84.

    PubMed  CAS  Google Scholar 

  216. Chu Z, Chen J-S, Liau C-T, et al. Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients. Anticancer Drugs. 2008;19(3):275–81.

    PubMed  CAS  Google Scholar 

  217. Malingré MM, Beijnen JH, Rosing H, et al. Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br J Cancer. 2001;84(1):42–7.

    PubMed  Google Scholar 

  218. Koolen SLW. Intravenous-to-oral switch in anticancer chemotherapy; focus on taxanes and gemcitabine [dissertation]. Utrecht: University of Utrecht; 2011. p. 105–16.

  219. Hanmi Pharmaceutical Company. Clinical trial to determine the maximum tolerated dose and to assess the safety and pharmacokinetic profile of oral paclitaxel in patients with advanced solid cancer [NCT01491204]. US National Institutes of Health. http://www.clinicaltrials.gov. Accessed 10 Jul 2012.

  220. Malingré MM, Richel DJ, Beijnen JH, et al. Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol. 2001;19(4):1160–6.

    PubMed  Google Scholar 

  221. Malingré MM, Ten Bokkel Huinink WW, Mackay M, et al. Pharmacokinetics of oral cyclosporin A when co-administered to enhance the absorption of orally administered docetaxel. Eur J Cin Pharmacol. 2001;57(4):305–7.

    Google Scholar 

  222. Koolen SLW, Oostendorp RL, Beijnen JH, et al. Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancer. Br J Clin Pharmacol. 2010;69(5):465–74.

    PubMed  CAS  Google Scholar 

  223. Kuppens IELM, Bosch TM, Van Maanen MJ, et al. Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093). Cancer Chemother Pharmacol. 2005;55(1):72–8.

    PubMed  CAS  Google Scholar 

  224. Hande K, Messenger M, Wagner J, et al. Inter- and intrapatient variability in etoposide kinetics with oral and intravenous drug administration. Clin Cancer Res. 1999;5(10):2742–7.

    PubMed  CAS  Google Scholar 

  225. Yong WP, Desai AA, Innocenti F, et al. Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer. Cancer Chemother Pharmacol. 2007;60(6):811–9.

    PubMed  CAS  Google Scholar 

  226. Reif S, Nicolson MC, Bisset D, et al. Effect of grapefruit juice intake on etoposide bioavailability. Eur J Clin Pharmacol. 2002;58(7):491–4.

    PubMed  CAS  Google Scholar 

  227. Herben VM, Rosing H, Ten Bokkel Huinink WW, et al. Oral topotecan: bioavailability and effect of food co-administration. Br J Cancer. 1999;80(9):1380–6.

    PubMed  Google Scholar 

  228. Kuppens IELM, Witteveen EO, Jewell RC, et al. A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients. Clin Cancer Res. 2007;13(11):3276–85.

    PubMed  CAS  Google Scholar 

  229. Kruijtzer CMF, Beijnen JH, Rosing H, et al. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol. 2002;20(13):2943–50.

    PubMed  CAS  Google Scholar 

  230. European Medicines Agency. Hycamtin. Summary of product characteristics (SPC). http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000123/human_med_000823.jsp&mid=WC0b01ac058001d124. Accessed 3 Aug 2012.

  231. Robert J. Clinical pharmacokinetics of idarubicin. Clin Pharmacokinet. 1993;24(4):275–88.

    PubMed  CAS  Google Scholar 

  232. Bauer KS, Karp JE, Garimella TS, et al. A phase I and pharmacologic study of idarubicin, cytarabine, etoposide, and the multidrug resistance protein (MDR1/Pgp) inhibitor PSC-833 in patients with refractory leukemia. Leuk Res. 2005;29(3):263–71.

    PubMed  CAS  Google Scholar 

  233. Pea F, Damiani D, Michieli M, et al. Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia. Eur J Clin Pharmacol. 1999;55(5):361–8.

    PubMed  CAS  Google Scholar 

  234. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989;16(4):215–37.

    PubMed  CAS  Google Scholar 

  235. Saif MW, Rosen LS, Saito K, et al. A phase I study evaluating the effect of CDHP as a component of S-1 on the pharmacokinetics of 5-fluorouracil. Anticancer Res. 2011;31(2):625–32.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

J. Beijnen and J. Schellens received a grant for translational research (ZonMw code 40-41200-98-004). B. Nuijen, J. Beijnen, and J. Schellens have patents for oral taxane formulations. No sources of funding were used to assist in the preparation of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jos H. Beijnen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stuurman, F.E., Nuijen, B., Beijnen, J.H. et al. Oral Anticancer Drugs: Mechanisms of Low Bioavailability and Strategies for Improvement. Clin Pharmacokinet 52, 399–414 (2013). https://doi.org/10.1007/s40262-013-0040-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-013-0040-2

Keywords

Navigation