Summary
During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2β) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2β on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration x time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157. ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant.
Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.
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References
Bedikian AY, Valdivieso M, Bodey GP, Freireich EJ (1979) Initial clinical studies with bruceantin. Cancer Treat Rep 63:1843
Castles TR, Bhandari JC, Lee CC, et al. (1976) Preclinical toxicologic evaluation of bruceantin (NSC 165563) in mice, dogs, and monkeys. U.S. National Technical Information Service, Springfield (PB-257175), p 348
Douros J, Suffness M (1978) New natural products of interest under development at the National Cancer Institute. Cancer Chemother Pharmacol 1:91
Fong KLL, Ho DHW, Carter CJK, Brown NS, Benjamin RS, Freireich EJ, Bodey GP Sr (1980) Radioimmunoassay for the detection and quantitation of bruceantin. Anal Biochem 105:281
Fresno M, Gonzales A, Vazques D, Jimenez A (1978) Bruceantin, a novel inhibitor of peptide bond formation. Biochim Biophys Acta 518:104
Garnick MB, Blum RH, Canellos GP, Mayer RJ, Parker L, Skarin AT, Li FP, Henderson C, Frei E III (1979) Phase I trial of bruceantin. Cancer Treat Rep 63:1929
Hartwell JL (1976) Types of anticancer agents isolated from plants. Cancer Treat Rep 60:1031
Kupchan SM, Britton RW, Ziegler MF, Sigel CW (1973) Bruceantin, a new potent antileukemic simaroubolide from Brucea antidysenterica. J Org Chem 38:178
Kupchan SM, Britton RW, Lacadie JA, Ziegler MF, Sigel CW (1975) The isolation and structural elucidation of bruceantin and bruceantinol, new potent antileukemic quassinoids from Brucea antidysenterica. J Org Chem 46:648
Liao LL, Kupchan SM, Horwitz SB (1976) Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis. Mol Pharmacol 12:167
Liesmann J, Belt RJ, Haas CD, Hoogstraten B (1981) Phase I study on bruceantin administered on a weekly schedule. Cancer Treat Rep 65:883
Loo JCK, Riegelmann S (1970) Assessment of pharmacokinetic constants from post-infusion blood curves obtained after IV infusion. J Pharm Sci 59:53
Ritschel WA (1976) Pharmacokinetics of single dose administration. In: Handbook of basic pharmacokinetics. Drug Intelligence, Hamilton, p 201
Sokal RR, Rohlf FJ (1969) Assumption of analysis of variance: In: Biometry, the principles and practice of statistics in biological research. W. H. Freeman, San Francisco, p 391
Suling WJ, Woolley CW, Shannon WM (1979) Disposition and metabolism of bruceantin in the mouse. Cancer Chemother Pharmacol 3:171
Wilkinson GR, Schenker S (1975) Drug disposition and liver disease. Drug Metab Rev 4:139
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Fong, K.L.L., Ho, D.H.W., Benjamin, R.S. et al. Clinical pharmacology of bruceantin by radioimmunoassay. Cancer Chemother. Pharmacol. 9, 169–172 (1982). https://doi.org/10.1007/BF00257747
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DOI: https://doi.org/10.1007/BF00257747