Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Jiangwei, Zhang; Ge, Guangbo; Liu, Yong; Wang, Liming; Liu, Xing-Bao; Zhang, Yanyan; Li, Wei; He, Yuqi; Wang, Zhengtao; Sun, Jie; Xiao, Hongbin; Yang, Ling

doi:10.1124/dmd.107.018242

Cited by 26 publications

(21 citation statements)

References 37 publications

(53 reference statements)

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“…By comparing the ratio of V max / K m , the formation of 6a-hydroxypaclitaxel was almost 9 times faster than that of p-39-hydroxypaclitaxel, suggesting that CYP2C8-mediated paclitaxel hydroxylation was more predominant in the current batch of pooled HLM. The K m and V max values observed in the present study were within 2-fold to 3-fold of the published results; this is not surprising given that laboratory-to-laboratory variability is often seen for in vitro metabolism studies (Polasek et al, 2004;Zhang et al, 2008). The differences in K m and V max values might be due to different HLM sources as well as the incubation conditions.…”

Section: Resultssupporting

confidence: 68%

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

Wang

Pan

et al. 2014

Drug Metab Dispos

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Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug-drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of K i values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathwaydependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a K I of 0.93 mM and k inact of 0.0137 min 21 , and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate (s). Using a static model, a reasonably accurate prediction of drug-drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients.

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Section: Resultssupporting

confidence: 68%

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

Wang

Pan

et al. 2014

Drug Metab Dispos

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“…Meanwhile, CYP3A4 instead of CYP2C8 becomes the primary monooxygenase. The present authors' recent study on the metabolic profile of cephalomannine (Figure 1, V) also suggested that relatively minor modification of the taxane molecule at C-3′ has a major consequence on the regioselective metabolism mediated by CYP3A4 (Zhang et al 2008a). Furthermore, the presence of an acetyl group at C-10 of the taxane ring strikingly activates hydroxylation by both CYP2C8 and CYP3A4 (Cresteil et al 2002).…”

Section: Introductionmentioning

confidence: 77%

“…The eluent was monitored at 227 nm with a flow rate of 1 ml min −1 . Commercial standards for the unknown metabolites of 7-epi-cephalomannine and 7-epi-10-deacetyl-paclitaxel were not available, and all detected metabolites contained the taxane ring as a chromophore (Gut et al 2006); therefore, 7-epi-cephalomannine and 7-epi-10-deacetyl-paclitaxel were used as standards, assuming an identical molar extinction coefficient, as described previously (Vaclavikova et al 2004;Zhang et al 2008a).…”

Section: Lc/ms Methodsmentioning

confidence: 99%

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

Zhang¹,

Liu²,

Zhang³

et al. 2009

Xenobiotica

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Taxanes exhibit a high tendency to epimerize at C-7 under physiological conditions. This study aimed to investigate the composite effect of C-7 configuration and other substructural elements on the metabolic properties of taxanes. Cephalomannine, 7-epi-cephalomannine, 10-deacetyl-paclitaxel, and 7-epi-10-deacetyl-paclitaxel were chosen as model compounds. In human liver microsomes, 7-epi-cephalomannine was subject to C-13 lateral chain (M-1) and diterpenoid core monohydroxylation (M-2), mediated by cytochrome P450 (CYP) 3A4 and CYP2C8, respectively. However, only one 7-epi-10-deacetyl-paclitaxel metabolite (M), monohydroxylated at taxane ring by CYP2C8, was detected. In comparison with cephalomannine, the catalytic efficiency of CYP2C8 for 7-epi-cephalomannine was about five-fold higher due to the decreased K(m). Although CYP2C8 showed a high capacity for metabolizing 7-epi-10-deacetyl-paclitaxel, 10-deacetyl-paclitaxel was hardly metabolized under the identical incubation conditions. In conclusion, C-7 configuration represents one of the most important structural determinants in taxanes metabolism.

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“…It is interesting to note that when both phenyl and benzamide at C3Ј of C13 side chain were replaced by N-␣-tert-butyloxycarbonyl amino group and an alkyl or alkenyl group, respectively, the major hydroxylation site was again moved from tert-butyl to the alkyl group (Frapolli et al, 2006;Gut et al, 2006). Zhang et al (2008) investigated how different substitutes at the C3Ј position of taxane analogs affected its metabolism with cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3Ј position. Their results showed that relatively minor modification of taxane at C3Ј has a major consequence on the metabolism.…”

Section: Discussionmentioning

confidence: 99%

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)

Zhang

Ly²,

Lago³

et al. 2009

Drug Metab Dispos

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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

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Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Cited by 26 publications

References 37 publications

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

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

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)

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