TY - JOUR T1 - CYP3A4-Mediated Ester Cleavage as the Major Metabolic Pathway of the Oral Taxane 3′-<em>tert</em>-Butyl-3′-<em>N</em>-<em>tert</em>-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-<em>N</em>-debenzoyl-4-<em>O</em>-methoxycarbonyl-paclitaxel (BMS-275183) JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 710 LP - 718 DO - 10.1124/dmd.108.024398 VL - 37 IS - 4 AU - Donglu Zhang AU - Van T. Ly AU - Michael Lago AU - Yuan Tian AU - Jinping Gan AU - W. Griffith Humphreys AU - S. Nilgün Çömezoğlu Y1 - 2009/04/01 UR - http://dmd.aspetjournals.org/content/37/4/710.abstract N2 - 3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183) is an orally available taxane analog that has the potential to be used as an oral agent to treat cancers. The compound is similar to the two clinically intravenously administered taxanes, paclitaxel and docetaxel, in that it contains a baccatin ring linked to a side chain through an ester bond. Unlike the other taxanes, the hydrolysis of this ester bond leads to formation of a free baccatin core (M13) that was the major metabolism pathway in incubations of [14C]BMS-275183 in human liver microsomes (HLMs) in the presence of NADPH, but it was not formed in incubations with human liver cytosol or HLM in the absence of NADPH. The other prominent metabolites formed in HLM incubations resulted from oxidation of t-butyl groups on the side chain (M20, M20B, M21, M22, and M23). All these metabolites were formed by cDNA-expressed CYP3A and not by other cytochrome P450 (P450) enzymes tested. Formation of these metabolites was selectively inhibited by ketoconazole and troleandomycin. The formation of M13 followed Michaelis-Menten kinetics with the Km values of 1.3 to 2.4 μM in HLM or CYP3A4; the Vmax value for the formation of M13 and M23 in the cDNA-expressed CYP3A4 matched well (within 2-fold difference) with that determined in HLM when expressed in units of per picomole of P450. These results showed that BMS-275183 is metabolized by CYP3A4 to yield baccatin through oxidation of side-chain t-butyl groups. An intramolecular cyclization of a side-chain hydroxylation metabolite is proposed to be responsible for the formation of M13, the side-chain hydrolysis metabolite. The American Society for Pharmacology and Experimental Therapeutics ER -