Altered Pharmacokinetics of Paclitaxel in Experimental Hepatic or Renal Failure
- 130 Downloads
The aim of this study was to investigate the effect of hepatic or renal insufficiency on the pharmacokinetics of paclitaxel in rats.
Rats were treated with carbon tetrachloride (CCl4; 0.5 ml/kg) to induce hepatic failure or were subjected to 5/6 nephrectomy (5/6 Nx) to induce renal failure. Paclitaxel (3 mg/kg) was administered intravenously or intraportally. Testosterone 6β-hydroxylase activity, which is a marker of CYP3A activity, was measured in rat liver microsomes from CCl4-treated or 5/6 Nx rats.
After paclitaxel was administered intravenously, total body clearance was significantly reduced by 73% and 34% relative to each control value in CCl4-treated and 5/6 Nx rats, respectively (control, 1.82 ± 0.42 vs. CCl4-treated, 0.49 ± 0.11; sham, 1.54 ± 0.07 vs. 5/6 Nx, 1.01 ± 0.12 L h−1 kg−1; mean ± SE, n = 5 to 6). Testosterone 6β-hydroxylase activity was reduced by 92% and 59% relative to each control value in rat liver microsomes from CCl4-treated and 5/6 Nx rats, respectively. After the intraportal administration of paclitaxel, apparent clearance was reduced by 85% relative to control value in rats with hepatic failure, while that in rats with renal failure was the same as the reduction in systemic clearance.
These results suggested that not only hepatic failure but also renal failure could modify the pharmacokinetics of paclitaxel in vivo.
Key words:hepatic failure 5/6 nephrectomy paclitaxel pharmacokinetics renal failure
area under the plasma concentration-time curve
high-performance liquid chromatography
- 5/6 Nx
Unable to display preview. Download preview PDF.
- 1.1. E. K. Rowinsky and R. C. Donehower. Paclitaxel (Taxol). N. Engl. J. Med. 332:1004–1014 (1995).Google Scholar
- 2.2. D. S. Sonnichsen, Q. Liu, E. G. Schuetz, J. D. Schuetz, A. Pappo, and M. V. Relling. Variability in human cytochrome P450 paclitaxel metabolism. J. Pharmcol. Exp. Ther. 275:566–575 (1995).Google Scholar
- 3.3. D. S. Sonnichsen and M. V. Relling. Clinical pharmacokinetics of paclitaxel. Clin. Pharmacokinet. 27:256–269 (1994).Google Scholar
- 4.4. L. Gianni, C. M. Kearns, A. Giani, G. Capri, L. Viganó, A.Locatelli, G. Bonadonna, and M. J. Egorin. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/ pharmacodynamic relationships in humans. J. Clin. Oncol. 13: 180–190 (1995).Google Scholar
- 5.5. T. Ohtsu, Y. Sasaki, T. Tamura, Y. Miyata, H. Nakanomyo, Y. Nishiwaki, and N. Saijo. Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clin. Cancer Res. 1:599–606 (1995).Google Scholar
- 6.6. M. T. Huizing, G. Giaccone, L. J. C. van Warmerdam, H. Rosing, P. J. M. Bakker, J. B. Vermorken, P. E. Postmus, N. van Zandwijk, M. G. J. Koolen, W. W. ten Bokkel-Huinink, W. J. F. van der Vijg, F. J. Bierhorst, A. Lai, O. Dalesio, H. M. Pinedo, C. H. N. Veenhof, and J. H. Beijnen. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. J. Clin. Oncol. 15:317– 329 (1997).Google Scholar
- 7.7. V. Rodighiero. Effects of liver disease on pharmacokinetics. An update. Clin. Pharmacokinet. 37:399–431 (1999).Google Scholar
- 8.8. M.-C. Bastien, F. Leblond, V. Pichette, and J.-P. Villeneuve. Differential alteration of cytochrome P450 isozymes in two experimental models of cirrhosis. Can. J. Physiol. Pharmacol. 78:912– 919 (2000).Google Scholar
- 9.9. V. R. N. Panday, M. T. Huizing, P. H. B. Willemse, A. De-Graeff, W. W. ten Bokkel-Huinink, J. B. Vermorken, and J. H. Beijnen. Hepatic metabolism of paclitaxel and its impact in patients with altered hepatic function. Semin. Oncol. 24:34–38 (1997).Google Scholar
- 10.10. R. Bruno, R. Olivares, J. Berille, P. Chaikin, N. Vivier, L. Hammershaimb, G. R. Rhodes, and J. R. Rigas. α-1-Acid glycoprotein as an independent predictor for treatment effects and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel. Clin. Cancer Res. 9:1077–1082 (2003).Google Scholar
- 11.11. T. P. Gibson. Influence of renal disease on pharmacokinetics. In W. E. Evans, L. J. Schentag, and W. J. Jusko (eds.), Applied Pharmacokinetics, 2nd ed, Applied Therapeutics, Washington, DC, 1986, pp. 83–115Google Scholar
- 12.12. F. A. Leblond, L. Giroux, J.-P. Villeneuve, and V. Pichette. Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab. Dispos. 28:1317–1320 (2000).Google Scholar
- 13.13. T. C. Dowling, A. E. Briglia, J. C. Fink, D. S. Hanes, P. D. Light, L. Stackiewicz, C. S. Karyekar, N. D. Eddington, M. R. Weir, and W. L. Henrich. Characterization of hepatic cytochrome P4503A activity in patients with end-stage renal disease. Clin. Pharmacol. Ther. 73:427–434 (2003).Google Scholar
- 14.14. S.-S. Hong, S.-J. Chung, and C.-K. Shim. Functional impairment of sinusoidal membrane transport of organic cations in rats with CCl4-induced hepatic failure. Pharm. Res. 17:833–838 (2000).Google Scholar
- 15.15. L. Ji, S. Masuda, H. Saito, and K. Inui. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int. 62:514–524 (2002).Google Scholar
- 16.16. M. Sugiura, K. Iwasaki, H. Noguchi, and R. Kato. Evidence for the involvement of cytochrome P-450 in tiaramide N-oxide reduction. Life Sci. 15:1433–1442 (1974).Google Scholar
- 17.17. R. W. Wang, D. J. Newton, T. D. Scheri, and A. Y. H. Lu. Human cytochrome P450 3A4-catalyzed testosterone 6β-hydroxylation and erythromycin N-demethylation. Drug Metab. Dispos. 25:502– 507 (1997).Google Scholar
- 18.18. T. Iwahori, T. Matsuura, H. Maehashi, K. Sugo, M. Saito, M. Hosokawa, K. Chiba, T. Masaki, H. Aizaki, K. Ohkawa, and T. Suzuki. CYP3A4 inducible model for in vitro analysis of human drug metabolism using a bioartificial liver. Hepatology 37:665– 673 (2003).Google Scholar
- 19.19. T. A. Willey, E. J. Bekos, R. C. Gaver, G. F. Duncan, L. K. Tay, J. H. Beijnen, and R. H. Farmen. High-performance liquid chromatographic procedure for the quantitative determination of paclitaxel (Taxol®) in human plasma. J. Chromatogr. 621:231–238 (1993).Google Scholar
- 20.20. J.-S. Choi. Pharmacokinetics of paclitaxel in rabbits with carbon tetrachloride-induced hepatic failure. Arch. Pharm. Res. 25:937– 977 (2002).Google Scholar
- 21.21. H. Okabe, I. Yano, Y. Hashimoto, H. Saito, and K. Inui. Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction. J. Pharm. Pharmacol. 54:65–70 (2002).Google Scholar
- 22.22. C. D. Anderson, J. Wang, G. N. Kumar, J. M. Mcmillan, U. K. Walle, and T. Walle. Dexamethasone induction of taxol metabolism in the rat. Drug Metab. Dispos. 23:1286–1290 (1995).Google Scholar
- 23.23. H. Okabe, M. Hasunuma, and Y. Hashimoto. The hepatic and intestinal metabolic activities of P450 in rats with surgery- and drug-induced renal dysfunction. Pharm. Res. 20:1591–1594 (2003).Google Scholar
- 24.24. A. Sparreboom, J. van Asperen, U. Mayer, A. H. Schinkel, J. W. Smit, D. K. F. Meijer, P. Borst, W. J. Nooijen, J. H. Beijnen, and O. van Tellingen. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc. Natl. Acad. Sci. USA 94:2031–2035 (1997).Google Scholar
- 25.25. M. R. Feng, J. Loo, and J. Wright. Disposition of the antipsychotic agent CI-1007 in rats, monkeys, dogs, and human cytochrome P450 2D6 extensive metabolizers. Drug Metab. Dispos. 26:982–988 (1998).Google Scholar
- 26.26. M. Gibaldi and D. Perrier. Clearance concepts. In M. Gibaldi and D. Perrier (eds.), Pharmacokinetics, Marcel Dekker, New York, 1982, pp. 319–353.Google Scholar
- 27.27. R. Vanholder, N. van Landschoot, R. De-Smet, A. Schoots, and S. Ringoir. Drug protein binding in chronic renal failure: evaluation of nine drugs. Kidney Int. 33:996–1004 (1988).Google Scholar
- 28.28. R. Gugler, D. W. Shoeman, D. H. Huffman, J. B. Cohlmia, and D. L. Azarnoff. Pharmacokinetics of drugs in patients with the nephrotic syndrome. J. Clin. Invest. 55:1182–1189 (1975).Google Scholar
- 29.29. G. N. Kumar, U. K. Walle, K. N. Bhalla, and T. Walle. Binding of taxol to human plasma, albumin and α1-acid glycoprotein. Res. Commun. Chem. Pathol. Pharmacol. 80:337–344 (1993).Google Scholar
- 30.30. H. J. G. D. van den Bongard, E. M. Kemper, O. van Tellingen, H. Rosing, R. A. A. Mathôt, J. H. M. Schellens, and J. H. Beijnen. Development and validation of a method to determine the unbound paclitaxel fraction in human plasma. Anal. Biochem. 324: 11–15 (2004).Google Scholar