Abstract
We investigated cytochrome P450 (P450)-catalyzed metabolism of the important cancer drugs paclitaxel and docetaxel in rat, pig, minipig, and human liver microsomes and cDNA-expressed P450 enzymes. In rat microsomes, paclitaxel was metabolized mainly to C3′-hydroxypaclitaxel (C3′-OHP) and to a lesser extent to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP), and another unknown monohydroxylated paclitaxel. In pig and minipig microsomes, this unknown hydroxypaclitaxel was the main metabolite, whereas C3′-OHP was a minor product. In minipigs, C2-OHP was the next minor product. In human liver microsomes, 6α-hydroxypaclitaxel (6α-OHP) was the main metabolite, followed by C3′-OHP and C2-OHP. Among different cDNA-expressed human P450 enzymes (CYP1A2, 1B1, 2A6, 2C9, 2E1, and 3A4), only CYP3A4 enzyme formed C3′-OHP and C2-OHP. Docetaxel was metabolized in pig, minipig, rat, and human liver microsomes mainly to hydroxydocetaxel (OHDTX), whereas CYP3A-induced rat microsomes produced primarily diastereomeric hydroxyoxazolidinones. Human liver microsomes from 10 different individuals formed OHDTX at different rates correlated with CYP3A4 content. Troleandomycin as a selective inhibitor of CYP3A inhibited the formation of C3′-OHP, C2-OHP, and di-OHP, as well as the unknown OHP produced in rat, minipig, and pig microsomes. In human liver microsomes, troleandomycin inhibited C3′-OHP and C2-OHP formation, and a suitable inhibitor of human CYP2C8, fisetin, strongly inhibited the formation of 6α-OHP, known to be catalyzed by human CYP2C8. In conclusion, the metabolism of docetaxel is the same in all four species, but metabolism of paclitaxel is different, and 6α-OHP remains a uniquely human metabolite. Pigs and minipigs compared with each other formed the same metabolites of paclitaxel.
Footnotes
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↵1 Abbreviations used are: C3′-OHP, C3′-hydroxypaclitaxel; P450, cytochrome P450; C2-OHP, C2-hydroxypaclitaxel; di-OHP, di-hydroxypaclitaxel; 6α-OHP, 6α-hydroxypaclitaxel; TAO, troleandomycin; PCN, pregnenolon-16α-carbonitrile; MS, mass spectrometry; MS/MS, tandem MS; tR, retention time; HPLC, high performance liquid chromatography; NPR, NADP(H)-cytochrome P450 reductase;
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This work was financed by Internal Grant Agency of the Ministry of Health of the Czech Republic Grants NL/6715-3 and NL/7567-3 (I.G., R.V., S.H., P.S.), U.S. Public Health Service Grants R01 CA90426 and P30 ES00267 (F.P.G.), and Grant Agency of the Czech Republic Grant 203/02/1152 (P.S.).
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Citation of meeting abstracts where the work was presented: Václavíková R, Horský S, and Gut I (2003) Interspecies variability of paclitaxel metabolism in humans, rats, minipigs and regular pigs, in XXII. Xenobiochemical Symposium, 2003 Jun 9–11, Smolenice, Slovak. Abstract in memorial volume Posters, Section 4, p. 51–52; Václavíková R, Horský S, and Gut I (2003) New in vitro metabolites of paclitaxel in humans, rats, minipigs and regular pigs and P450 involved in their formation, at the 13th International Conference on Cytochromes P450, 2003 Jun 29–Jul 3, Prague, Czech Republic. Abstract in Chemické Listy 97(6), S188, WP54; Václavíková R, Horský S, and Gut I, New in vitro metabolites of paclitaxel in humans, rats, minipigs and regular pigs. Proceedings: Cytochromes P450, Biochemistry, Biophysics and Drug Metabolism, Monduzzi Editore, International Proceedings division, Work Code D629C0043; Václavíková R, Svobodová S, Horský S, Šimek P, and Gut I (2003) Poster; Taxanes: antitumor effects and interspecies differences in metabolism. Active presentation of poster in EURO-TOX 2003, Sep 28–Oct 1, Florence, Italy.
- Received November 3, 2003.
- Accepted February 25, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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DIFFERENT IN VITRO METABOLISM OF PACLITAXEL AND DOCETAXEL IN HUMANS, RATS, PIGS, AND MINIPIGS
