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Hepatic Biotransformation of Docetaxel (Taxotereâ®)In Vitro: Involvement of the CYP3A Subfamily in Humans1

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Hepatic Biotransformation of Docetaxel (Taxotereâ®)In Vitro: Involvement of the CYP3A Subfamily in Humans1 [CANCER RESEARCH 56. 1296-13(12. March 15. 1996] Hepatic Biotransformation of Docetaxel (Taxotere®)in Vitro: Involvement of the CYP3A Subfamily in Humans1 FrançoiseMarre,2 Ger-Jan Sanderink,3 Georges de Sousa, Claude Gaillard, Michel Martinet, and Roger Rahmani3 Instituí National Je la Sanie et de la Recherche Médicale,4l Bd. du Cap. BP 2078. 06606 Antikes Cedex ¡F.M.. G. d. S.. K. R. l, and Rhône-Poulenc Rarer SA Recherche- Dí'vi'lupiienu'ní.Centre de Recherche de Viity-Alfonville, 3 Digue d'Alfortville. 94140 Alfortville ¡G-J.S., C. G., M. M.]. France ABSTRACT involved in the metabolism of drugs, the CYP4 superenzyme family was recognized early as the chief contributor. Currently, at least 15 Docetaxel metabolism mediated by cytochrome P450-dependent nio- human liver CYPs involved in drug metabolism have been character nooxygenases was evaluated in human liver microsomes and hepatocytes. ized in terms of molecular, spectral, enzymatic, and immunological In microsomes, the drug was converted into four major metabolites properties (9). This multigene superfamily of hemoproteins is in resulting from successive oxidations of the tert-butyl group on the syn volved in the deactivation and/or activation of numerous endogenous thetic side chain. Enzyme kinetics appeared to be biphasic with a Vmaxand apparent AMIfor the high-affinity site of 9.2 pmol/min/mg and 1.1 ;IM. substances (e.g., steroids and fatty acids) and xenobiotics (e.g., drugs, carcinogens). CYPs are involved directly in a number of drug-induced respectively. The intrinsic metabolic clearance in human liver microsomes (VmaJK„„8.4ml/min/g protein) was comparable to that in rat and dog hepatotoxicities and drug interactions. Some of these adverse effects liver microsomes, but lower than in mouse liver microsomes. are caused by genetic polymorphism. Others result either from drug Although the metabolic profile was identical in all subjects, a large interactions occurring between several coadministered drugs that are quantitative variation in docetaxel biotransformation rates was found in a metabolized by the same CYP. or from the specific induction of the human liver microsome library, with a ratio of 8.9 in the highest:lowest CYP in question. Thus, understanding the role of the CYPs involved in a given drug's metabolism and their regulation will be useful in biotransformation rates. Docetaxel biotransformation was correlated sig nificantly (0.7698; P < 0.0001) with erythromycin A'-demethylase activity, determining the range of interindividual variability in drug response but not with aniline hydroxylase or debrisoquine 4-hydroxylase. It was and avoiding undesirable drug interactions. This is a matter of par inhibited, both in human hepatocytes and in liver microsomes, by typical ticular concern in cancer chemotherapy, in which many prescriptions CYP3A substrates and/or inhibitors such as erythromycin, ketoconazole, may be encountered simultaneously. Therefore, since most anticancer nifedipine, midazolam, and troleandomycin. Docetaxel metabolism was drugs produce a number of side effects, a better understanding of the induced in vitro in human hepatocytes by dexamethasone and rifampicin, enzyme systems that process these compounds would be of great use both classical CYP3A inducers. These data suggest a major role of liver in designing optimal therapy protocols. cytochrome P450 isoenzymes of the CYP3A subfamily in docetaxel bio To date, research on the identification of specific CYP isozymes in transformation in humans. Finally, some Vinca alkaloids and doxorubicin the metabolism of cancer chemotherapeutic agents has been limited to were shown to inhibit docetaxel metabolism in human hepatocytes and a few compounds such as CYCLO or procarbazine, where rat hepatic liver microsomes. These findings may have clinical implications and microsomes were used (10). Except for some very recent studies on should be taken into account in the design of combination cancer chem Vinca alkaloids and paclitaxel (11-13), little data on the human otherapy regimens. enzymes involved in the metabolism of cancer chemotherapeutic agents are available. In that context, we evaluated the biotransforma INTRODUCTION tion of docetaxel by using microsomes and/or hepatocytes from hu man livers. The aim of the present report was to identify hepatic CYP Docetaxel (Taxotere®,RP 56976; Fig. 1), a semisynthetic taxoid, is isozymes involved in docetaxel biotransformation in humans and to an antimitotic agent belonging to the spindle poison family (1). The evaluate possible metabolic drug interactions between docetaxel and drug promotes the assembly of stable microtubules in vitro and is an other anticancer agents, which are potentially associated with this inhibitor of cell replication (2). The compound has demonstrated taxoid. excellent antitumor activity against various types of solid tumors in preclinical models (3, 4) and is currently undergoing Phase II and III MATERIALS AND METHODS clinical evaluation. The pharmacokinetics of docetaxel has been stud ied after i.v. infusion in mice, rat, dogs, and cancer patients and Chemicals. Docetaxel (Taxotere®;RP56976. batch PH12512), DZP. IMI, showed multiphasic disposition profiles with rapid initial tissue up INTO (RP60475), PB, RANI, and DOXO were obtained from the Centre de Recherche of Rhône-Poulenc Rorer SA (Vitry-sur-Seine. France). take and large volumes of distribution. In these species, the drug is [14C]Docetaxel (specific activity, 50 mCi/mmol) was synthesized by the Cen eliminated almost exclusively by hepatic metabolism and biliary tre des Etudes Nucléaires(Gif-sur-Yvette, France). a-NF, /3-NF, ANI, BP, excretion, with quite similar metabolic profiles. The parent drug is the CIME. DEX, ERY, KETO, NADPH, NIF, propranolol, QUI, SPA. TP, TB. main circulating compound, and metabolites of docetaxel described and TAO were purchased from Sigma (Saint Quentin Fallavier, France). DBQ. thus far are much less cytotoxic (4-8). MDZ, and SKF525A (proadifen) were a gracious gift from Hoffmann LaRoche Metabolism represents a major factor of variability in drug response (Basel, Switzerland). ACET and QUIS were obtained from E. Merck; CAP and toxicity particularly for anticancer compounds that exhibit a narrow therapeutic index. Among the various hepatic enzyme systems 4 The abbreviations used are: CYP, cytochrome P450; DZP. dia/.epam; IMI, imipra- mine; INTO, intoplicine: PB. phénobarbital; RANI, ranitidine; DOXO. doxorubicin; a-NF, a-naphtoflavone; ß-NF. ß-naphtoflavone: ANI. aniline; BP, ben/o[«]pyrene; Received 5/2/95; accepted 1/15/96. CIME, cimetidine: DEX, dexamethasone; ERY. erythromycin: KETO. keloconazole: NIF, The costs of publication of this article were defrayed in part by the payment of page nifedipine; QUI, quinidine: SPA. spancine; TP. theophylline: TB. tolbutamide: TAO. charges. This article must therefore he hereby marked advertisement in accordance with troleandomycin; DBQ, debrisoquine; 3MC, 3-methylcholanthrene: MDZ. mida/.olam; 18 U.S.C. Section 1734 solely to indicate this fact. ACET, acetanilide; VP16, etoposide; QUIS. quinine sulfate; CAF. caffeine; CISPT, 1This work was supported in part by a grant from Ligue Nationale Contre le Cancer. cisplatin; CYCLO, cyclophosphamide; 5-FU, 5-fluorouracil: HB. hexobarbilal: VRB, * Present address: Laboratoire de Biochimie, Facultéde Pharmacie. 2 rue du Dr vinorelbine; OME, omeprazole: IC^,,, 50% inhibitory concentration; VCR. vincristine; Raymond Marcland, 87025 Limoges Cedex. France. VBL, vinblastine: HPLC, high-performance liquid chromatography: PARA, paracetamol; 3 To whom requests for reprints should be addressed. HBSS. Hank's balanced salt solution. 1296 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1996 American Association for Cancer Research. HEPATIC CYP3A-MEDIATED DOCETAXEL METABOLISM 1200 T studies were performed to determine apparent K, values; microsomal fractions were incubated for 30 min with 1. 2.5, and 5 /UMdocetaxel and 0.5, 1, 2, 5, and 10 UM KETO. 1000 •¿ Human liver microsomal fractions were also characterized by using specific substrates of several CYP isoforms. ERY iV-demethylase activity was deter mined by colorimetrie estimation of the formaldehyde formed after a 20-min 800 •¿ incubation period of microsomal fractions ( 1 mg microsomal protein/ml) with 2 mM ERY (17). ANI hydroxylase and DBQ 4-hydroxylase activities were determined as described previously (18. 19). CPM 600 •¿ Hepatocyte Isolation and Use of Primary Culture. A discarded human hepatic tissue fragment from a patient with secondary hepatic tumor (IU 46) and normal hepatic fragments (HL 45. 50, and 51) were obtained from the 400 •¿â€¢¿ Sainte Marguerite Hospital (Professor P. Fuentes and Dr. P. Thomas. Mar seille, France). After the tissue was washed with HBSS. hepatocytes were isolated by conventional collagenase perfusion as described previously (20). 200 -• Using such a method, viability of cells, determined by erythrosine B exclusion test, was at least 80%. After washing (three times) with L15 medium, cells were resuspended in William's E medium supplemented with PCS (10%), insulin (0.1 lU/ml). 20 40 penicillin (50 lU/ml). streptomycin (50 tig/ml), and netilmicine (50 tig/ml). Hepatocytes were seeded in 6-well (800,000 cells/well) and I2-well (300.000 Fig. I. HPLC metabolic- pattern of docetaxel in liver microsomes. Incubation time. 60 cells/well) plates precoated with collagen type I (200 and 100 tig/well, respec min: on-line radioactivity detection. VI. alcohol
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