CYP3A4-Mediated Ester Cleavage as the Major Metabolic Pathway of the Oral Taxane 3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183)

Abstract

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 Paclitaxel (Taxol, Bristol-Myers Squibb Co., Wallingford, CT), initially isolated in 1967 from the bark of the Pacific yew tree, Taxus brevifolia, showed an antitumor activity for a broad range of rodent tumors (Wall and Wani, 1995). Paclitaxel has become a widely used and effective chemotherapy agent to treat patients with lung, ovarian, and breast cancer and an advanced form of Kaposi's sarcoma (Saville et al., 1995;Rose et al., 2001). Together with docetaxel, paclitaxel forms the drug category of the taxanes. Taxanes, as well as recently marketed epothilone classes (Goel et al., 2008), stop cell division by inhibition of the microtubule function through stabilizing GDP-bound tubulin in the microtubule. Paclitaxel and docetaxel are administered to patients intravenously because of their poor oral bioavailability. Oral treatment with this class of chemotherapy agents would increase convenience to patients, reduce cost of administration, and allow the use of chronic treatment regimens.BMS-275183 was synthesized as a part of a program to identify taxanes with potential for oral use in the treatment of cancers (Bröker et al., 2007). The compound is a C-4 methyl carbonate analog of paclitaxel that contains additional modifications in the side chain where the two phenyl groups of paclitaxel were replaced by t-butyl groups (Bröker et al., 2007). BMS-275183 exhibited good oral bioavailability in both rat and dog and showed antitumor activity comparable with intravenous paclitaxel (Frapolli et al., 2006).[ 14 C]BMS-275183 was metabolized to oxidative metabolites in liver microsomes of animals and humans and in bile duct-cannulated rats Kim-Kang et al., 2002). Only trace amounts of conjugated metabolites were detected in rat bile. The major in vitro metabolites were identified as M13 (hydrolysis metabolite), M20 and M20B (a carbamate metabolite resulting from hydroxylation of the oxycarbonyl t-butyl group followed by cyclization or a lactol metabolite resulting from hydroxylation of the C3Ј t-butyl groups followed by cyclization), M21 (␥-lactone metabolite), M22 (a carboxylic acid metabolite), and M23 (an oxycarbonyl t-butyl hydroxylated metabolite). In contrast to 6␣-hydroxylation of the baccatin ring of paclitaxel, the major metabolic pathways in BMS-275183 mainly occurred by oxidation and hydrolytic cleavage of the side chain.Article, publication date, and citation information can be found at

Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica

“…The inhibitor concentration was 1 mM for ABT (Balani et al, 2004), 10 μM for NBN (Zhang et al, 2007; Kazui et al, 2010) and 2 μM for ketoconazole (Daneshmend and Warnock, 1988; Khojasteh et al, 2011). The suicide mechanism-dependent inhibitor ABT was first pre-incubated with HLM in the presence of NADPH for 20 minutes before the substrate was added (Zhang et al, 2009). NBN or ketoconazole was concurrently added with substrate to the reaction mixture.…”

C-7 configuration as one of determinants in taxanes metabolism by human cytochrome P450 enzymes

“…Investigation of the metabolic pathway of the oral taxane BMS-275183 provided other evidence that modification of the C-3′ substituent may change the major catalysing enzyme from CYP2C8 to CYP3A4 (Zhang et al 2009a). These observations probably resulted from the hydrophobic interactions between the phenyl of paclitaxel and the CYP2C8 peptide-chain (Cresteil et al 2002).…”

Characterization of in vitro metabolites of TM‐2, a potential antitumor drug, in rat, dog and human liver microsomes using liquid chromatography/tandem mass spectrometry

“…Careful mining of the data collected from the LC/LTQ Orbitrap MS system and the LC/QqQ‐MS system resulted in the discovery of 12 metabolites in microsomes samples. Metabolites were proposed in the light of their fragments and HPLC retention time by comparison with metabolites identified in other taxanes . Table shows the characterization of metabolites of TM‐2 from in vitro incubations in three species.…”

“…TM‐2 (2.0 μM) was incubated in liver microsomes (rat (RLMs), dog (DLMs) and human (HLMs), 0.3 mg protein mL −1 ) in the absence (control) and presence of known CYP isoform‐specific inhibitors. The inhibitor concentrations were 10 μM for α‐naphthoflavone (α‐NF, CYP1A2), 10 μM for methoxsalen (CYP2A6), 20 μM for quercetin (CYP2C8), 5 μM for quinidine (CYP2D6) and 5 μM for ketoconazole (CYP3A4) . Inhibition by methoxsalen (5 μM) for CYP2A6 was preincubated in the presence of NADPH for 20 min before the substrate was added.…”