Taxane's substituents at C3′ affect its regioselective metabolism

Different in vitro metabolism of cephalomannine and paclitaxel

Jiang Wei Zhang, Guang Bo Ge, Yong Liu, Li Ming Wang, Xing Bao Liu, Yan Yan Zhang, Wei Li, Yu Qi He, Zheng Tao Wang, Jie Sun, Hong Bin Xiao, Ling Yang

Research output: Contribution to journalArticle

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Abstract

To investigate how taxane's substituents at C3′ affect its metabolism, we compared the metabolism of cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3′ position. After cephalomannine was incubated with human liver microsomes in an NADPH-generating system, two monohydroxylated metabolites (M1 and M2) were detected by liquid chromatography/tandem mass spectrometry. C4″ (M1) and C6α (M2) were proposed as the possible hydroxylation sites, and the structure of M1 was confirmed by 1H NMR. Chemical inhibition studies and assays with recombinant human cytochromes P450 (P450s) indicated that 4″- hydroxycephalomannine was generated predominantly by CYP3A4 and 6α-hydroxycephalomannine by CYP2C8. The overall biotransformation rate between paclitaxel and cephalomannine differed slightly (184 vs. 145 pmol/min/mg), but the average ratio of metabolites hydroxylated at the C13 side chain to C6α for paclitaxel and cephalomannine varied significantly (15:85 vs. 64:36) in five human liver samples. Compared with paclitaxel, the major hydroxylation site transferred from C6α to C4″, and the main metabolizing P450 changed from CYP2C8 to CYP3A4 for cephalomannine. In the incubation system with rat or minipig liver microsomes, only 4″-hydroxycephalomannine was detected, and its formation was inhibited by CYP3A inhibitors. Molecular docking by AutoDock suggested that cephalomannine adopted an orientation in favor of 4″-hydroxylation, whereas paclitaxel adopted an orientation favoring 3′-p-hydroxylation. Kinetic studies showed that CYP3A4 catalyzed cephalomannine more efficiently than paclitaxel due to an increased Vm. Our results demonstrate that relatively minor modification of taxane at C3′ has major consequence on the metabolism.

Original languageEnglish (US)
Pages (from-to)418-426
Number of pages9
JournalDrug Metabolism and Disposition
Volume36
Issue number2
DOIs
StatePublished - Feb 1 2008

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Paclitaxel
Hydroxylation
Cytochrome P-450 CYP3A
Liver Microsomes
Miniature Swine
Biotransformation
Tandem Mass Spectrometry
cephalomannine
In Vitro Techniques
NADP
Liquid Chromatography
Cytochrome P-450 Enzyme System
Liver

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Taxane's substituents at C3′ affect its regioselective metabolism : Different in vitro metabolism of cephalomannine and paclitaxel. / Zhang, Jiang Wei; Ge, Guang Bo; Liu, Yong; Wang, Li Ming; Liu, Xing Bao; Zhang, Yan Yan; Li, Wei; He, Yu Qi; Wang, Zheng Tao; Sun, Jie; Xiao, Hong Bin; Yang, Ling.

In: Drug Metabolism and Disposition, Vol. 36, No. 2, 01.02.2008, p. 418-426.

Research output: Contribution to journalArticle

Zhang, JW, Ge, GB, Liu, Y, Wang, LM, Liu, XB, Zhang, YY, Li, W, He, YQ, Wang, ZT, Sun, J, Xiao, HB & Yang, L 2008, 'Taxane's substituents at C3′ affect its regioselective metabolism: Different in vitro metabolism of cephalomannine and paclitaxel', Drug Metabolism and Disposition, vol. 36, no. 2, pp. 418-426. https://doi.org/10.1124/dmd.107.018242
Zhang, Jiang Wei ; Ge, Guang Bo ; Liu, Yong ; Wang, Li Ming ; Liu, Xing Bao ; Zhang, Yan Yan ; Li, Wei ; He, Yu Qi ; Wang, Zheng Tao ; Sun, Jie ; Xiao, Hong Bin ; Yang, Ling. / Taxane's substituents at C3′ affect its regioselective metabolism : Different in vitro metabolism of cephalomannine and paclitaxel. In: Drug Metabolism and Disposition. 2008 ; Vol. 36, No. 2. pp. 418-426.
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