Abstract
Objective
Ibuprofen, a nonsteroidal anti-inflammatory agent, is metabolised in vitro by cytochrome P450 (CYP) 2C8 and 2C9. We studied the possible effect of gemfibrozil, an in vivo inhibitor of CYP2C8, on the pharmacokinetics of ibuprofen in healthy volunteers.
Methods
In a randomised two-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each subject ingested 400 mg of racemic ibuprofen. Plasma concentrations of ibuprofen enantiomers and gemfibrozil were measured.
Results
Gemfibrozil raised the mean total area under the plasma concentration-time curve (AUC0–∞) of R-ibuprofen by 34% (range −10 to 67%; P < 0.001). The elimination half-lives (t 1/2) of R- and S-ibuprofen were increased by 54 and 34% (range 11–162% and 16–85%; P < 0.001) respectively. The other pharmacokinetic variables of R- and S-ibuprofen were not changed significantly. The AUC0–∞ ratio of R-ibuprofen to S-ibuprofen was increased by gemfibrozil (P < 0.001).
Conclusions
Gemfibrozil moderately increases the AUC0–∞ of R-ibuprofen and prolongs its t 1/2, indicating that R-ibuprofen is partially metabolised by CYP2C8. The interconversion of R- to S-ibuprofen can explain the small effect of gemfibrozil on the t 1/2 of S-ibuprofen. The gemfibrozil-ibuprofen interaction is of limited clinical significance.
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References
Adams SS, Bresloff P, Mason CG (1976) Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the (−)-isomer. J Pharm Pharmacol 28:256–257
Evans AM (1992) Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs. Eur J Clin Pharmacol 42:237–256
Lee EJ, Williams K, Day R, Graham G, Champion D (1985) Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 19:669–674
Hamman MA, Thompson GA, Hall SD (1997) Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 54:33–41
Kirchheiner J, Meineke I, Freytag G, Meisel C, Roots I, Brockmöller J (2002) Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Clin Pharmacol Ther 72:62–75
Martínez C, García-Martín E, Blanco G, Gamito FJ, Ladero JM, Agúndez JA (2005) The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol 59:62–69
García-Martín E, Martínez C, Tabarés B, Frías J, Agúndez JA (2004) Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther 76:119–127
Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ (2002) Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos 30:1352–1356
Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ (2002) Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 72:685–691
Niemi M, Backman JT, Neuvonen M, Neuvonen PJ (2003) Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 46:347–351
Jaakkola T, Backman JT, Neuvonen M, Neuvonen PJ (2005) Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin Pharmacol Ther 77:404–414
Niemi M, Backman JT, Granfors M, Laitila J, Neuvonen M, Neuvonen PJ (2003) Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 46:1319–1323
Niemi M, Tornio A, Pasanen MK, Fredrikson H, Neuvonen PJ, Backman JT (2006) Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur J Clin Pharmacol 62:463–472
Wen X, Wang JS, Backman JT, Kivistö KT, Neuvonen PJ (2001) Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos 29:1359–1361
Lilja JJ, Backman JT, Neuvonen PJ (2005) Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects. Br J Clin Pharmacol 59:433–439
Pettersson KJ, Olsson A (1991) Liquid chromatographic determination of the enantiomers of ibuprofen in plasma using a chiral AGP column. J Chromatogr 563:414–418
Menzel-Soglowek S, Geisslinger G, Brune K (1990) Stereoselective high-performance liquid chromatographic determination of ketoprofen, ibuprofen and fenoprofen in plasma using a chiral alpha 1-acid glycoprotein column. J Chromatogr 532:295–303
Hengy H, Kölle EU (1985) Determination of gemfibrozil in plasma by high performance liquid chromatography. Arzneimittelforschung 35:1637–1639
Shitara Y, Hirano M, Sato H, Sugiyama Y (2004) Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther 311:228–236
Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, Toren P, Parkinson A (2006) Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab Dispos 34:191–197
Tan SC, Patel BK, Jackson SH, Swift CG, Hutt AJ (2002) Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers. Xenobiotica 32:683–697
Hynninen VV, Olkkola KT, Leino K, Lundgren S, Neuvonen PJ, Rane A, Valtonen M, Vyyryläinen H, Laine K (2006) Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(−)-ibuprofen. Antimicrob Agents Chemother 50:1967–1972
Tracy TS, Wirthwein DP, Hall SD (1993) Metabolic inversion of (R)-ibuprofen. Formation of ibuprofenyl-coenzyme A. Drug Metab Dispos 21:114–120
Bahadur N, Leathart JB, Mutch E, Steimel-Crespi D, Dunn SA, Gilissen R, Houdt JV, Hendrickx J, Mannens G, Bohets H, Williams FM, Armstrong M, Crespi CL, Daly AK (2002) CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol 64:1579–1589
Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, Goldstein JA (2001) Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 11:597–607
Niemi M, Leathart JB, Neuvonen M, Backman JT, Daly AK, Neuvonen PJ (2003) Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide. Clin Pharmacol Ther 74:380–387
Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Daly AK, Eichelbaum M, Kivistö KT, Neuvonen PJ (2005) Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther 77:468–478
Bidstrup TB, Damkier P, Olsen AK, Ekblom M, Karlsson A, Brøsen K (2006) The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide. Br J Clin Pharmacol 61:49–57
Pedersen RS, Damkier P, Brøsen K (2006) The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects. Br J Clin Pharmacol 62:682–689
Henningsson A, Marsh S, Loos WJ, Karlsson MO, Garsa A, Mross K, Mielke S, Vigano L, Locatelli A, Verweij J, Sparreboom A, McLeod HL (2005) Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res 11:8097–8104
Kirchheiner J, Thomas S, Bauer S, Tomalik-Scharte D, Hering U, Doroshyenko O, Jetter A, Stehle S, Tsahuridu M, Meineke I, Brockmöller J, Fuhr U (2006) Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype. Clin Pharmacol Ther 80:657–667
Yasar U, Lundgren S, Eliasson E, Bennet A, Wiman B, de Faire U, Rane A (2002) Linkage between the CYP2C8 and CYP2C9 genetic polymorphisms. Biochem Biophys Res Commun 299:25–28
Acknowledgements
This study was supported by grants from the Helsinki University Central Hospital Research Fund, the National Technology Agency, and the Sigrid Jusélius Foundation, Finland. None of the authors has any financial or personal relationships that could be perceived as influencing the research described.
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Tornio, A., Niemi, M., Neuvonen, P.J. et al. Stereoselective interaction between the CYP2C8 inhibitor gemfibrozil and racemic ibuprofen. Eur J Clin Pharmacol 63, 463–469 (2007). https://doi.org/10.1007/s00228-007-0273-9
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DOI: https://doi.org/10.1007/s00228-007-0273-9