Pharmacokinetics of oxaliplatin in humans
Oxaliplatin is a novel platinum complex used for the treatment of metastatic colorectal carcinoma. The pharmacokinetics of the free fraction of oxaliplatin in blood were evaluated in 10 patients given 85 mg/m2 of oxaliplatin using an infusion time of 2 h. Blood samples were collected during and after the infusion and immediately placed on ice. The samples were ultrafiltrated centripetally and the concentration of oxaliplatin in the ultrafiltrate was determined by liquid chromatography in combination with postcolumn derivatization. The in vitro degradation rate was determined in blood from the patients taken immediately before drug administration.
The maximal blood concentration (C max) and terminal half-life (t 1/2) were 1.44±0.20 (SD) µg/mL and 14.1 min (range: 10.2–24.5), respectively. The area under the blood concentration time curve (AUC), clearance (CL), and distribution volume (V ss) were (means±SD) 161±22 µg min/mL, 32.1±4.2 L/h/m2, and 0.26±0.06 L/kg, respectively. There was a significant correlation between the clearance of oxaliplatin in the patients and the degradation rate in whole blood (r=0.746; p=0.017).
Oxaliplatin has a short elimination half-life, which is in a sharp contrast to previously reported elimination half-lives obtained by analysis of the platinum content in plasma and ultrafiltrate. The correlation between in vivo and in vitro data suggests that the degradation in whole blood plays a role for the elimination of the drug.
Key WordsColorectal carcinoma oxaliplatin clearance degradation blood
Misset, J.L., Bleiberg, H., Sutherland, W., Bekradda, M. and Cvitkovic, E. (2000). Oxaliplatin clinical activity: a review. Crit. Rev. Oncol. Hematol.
Graham, M.A., et al. (2000). Clinical pharmacokinetics of oxaliplatin: a critical review. Clin. Cancer Res.
Allain, P., et al. (2000). Early biotransformations of oxaliplatin after its intravenous administration to cancer patients. Drug Metab. Dispos.
Andersson, A. and Ehrsson, H. (1994). Determination of cis-platin and cis
-diammineaquachloroplatinum(II) ion by liquid chromatography using post-column derivatization with diethyldithiocarbamate. J. Chromatogr. B
Boxenbaum, H.G., Riegelman, S. and Elashoff, R.M. (1974). Statistical estimations in pharmacokinetics. J. Pharmacokin. Biopharm.
Kern, W., et al. (1999). Oxaliplatin pharmacokinetics during a four-hour infusion. Clin. Cancer Res.
Massari, C., et al. (2000). Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function. Cancer Chemother. Pharmacol.
Luo, F.R., Wyrick, S.D. and Chaney, S.G. (1999). Biotransformations of oxaliplatin in rat blood in vitro. J. Biochem. Mol. Toxicol.
Woynarowski, J.M., et al. (2000). Oxaliplatin-induced damage of cellular DNA. Mol. Pharmacol.
Butour, J.L., Mazard, A.M. and Macquet, J.P. (1985). Kinetics of the reaction of cis-platinum compounds with DNA in vitro. Biochem. Biophys. Res. Commun.
Luo, F.R., Wyrick, S.D. and Chaney, S.G. (1998). Cytotoxicity, cellular uptake, and cellular biotransformations of oxaliplatin in human colon carcinoma cells. Oncol. Res.
Andersson, A., Fagerberg, J., Lewensohn, R. and Ehrsson, H. (1996). Pharmacokinetics of cisplatin and its monohydrated complex in humans. J. Pharm. Sci.
Andersson, A. and Ehrsson, H. (1995). Stability of cisplatin and its monohydrated complex in blood, plasma and ultrafiltrate—implications for quantitative analysis. J. Pharm. Biomed. Anal.