Stereoselective metabolism of rabeprazole-thioether to rabeprazole by human liver microsomes.
OBJECTIVE: Rabeprazole is metabolized mainly non-enzymatically to rabeprazole-thioether. This in vitro study was designed to clarify the stereoselective oxidation mechanism and to identify the enzyme(s) involved in the metabolic breakdown of rabeprazole-thioether to rabeprazole. METHODS: Rabeprazole-thioether was incubated with human liver microsomes and several recombinant cytochrome P450 ( CYP) enzymes (CYPs 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4). High-performance liquid chromatography was used for identification and quantification of each rabeprazole enantiomer. RESULTS: The K ( m ) and V ( max ) values for the formation of (R)-rabeprazole from rabeprazole-thioether in human liver microsomes were 6.6 muM and 92 pmol/min/mg protein, respectively, whereas those for the formation of (S)-rabeprazole were 5.1 muM and 21 pmol/min/mg protein, respectively. CYP3A4 was found to be the major enzyme responsible for (R)- and (S)-rabeprazole formation from rabeprazole-thioether. The intrinsic clearance (V ( max ) /K ( m )) for the oxidation by CYP3A4 of (R)-rabeprazole was 3.5-fold higher than that for the (S)-enantiomer (81 nl/min/pmol of P450 vs. 23 nl/min/pmol of P450). On the other hand, CYP2C19 and CYP2D6 were the main enzymes catalyzing the formation of desmethylrabeprazole-thioether from rabeprazole-thioether. The mean K ( m ) and V ( max ) values of desmethylrabeprazole-thioether formation for CYP2C19 were 5.1 muM and 600 pmol/min/nmol of P450, respectively, whereas those for CYP2D6 were 15.1 muM and 736 pmol/min/nmol of P450, respectively. DISCUSSION: Rabeprazole is reduced mainly non-enzymatically to rabeprazole-thioether, which is further stereoselectively re-oxidized by CYP3A4 mainly to (R)-rabeprazole. The difference in the enantioselective disposition of rabeprazole is determined by stereoselectivity in CYP3A4-mediated metabolic conversion from rabeprazole-thioether to rabeprazole.[1]References
- Stereoselective metabolism of rabeprazole-thioether to rabeprazole by human liver microsomes. Miura, M., Satoh, S., Tada, H., Habuchi, T., Suzuki, T. Eur. J. Clin. Pharmacol. (2006) [Pubmed]
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