Stereoselective <i>in vitro</i> metabolism of rhynchophylline and isorhynchophylline epimers of <i>Uncaria rhynchophylla</i> in rat liver microsomes

<p>1. The objective was to investigate the underlying mechanism of the stereoselectivity in the metabolism of rhynchophylline (RIN) and isorhynchophylline (IRN) epimers in rat liver microsomes (RLM).</p> <p>2. After incubation, eight metabolites of RIN (M1-5) and IRN (M6-8) reacted at A- and C-ring were identified using LC-Q-TOF/MS. Metabolic pathways included oxidation, hydroxylation, N-oxidation and dehydrogenation. In addition, hydroxylation at A-ring was the major metabolic pathway for RIN whereas the oxidation at C-ring was the major one for IRN.</p> <p>3. Enzyme kinetics showed that the intrinsic clearance (CL<sub>int</sub>) for IRN elimination was 1.9-fold higher than RIN and the degradation half-life (T<sub>1/2</sub>) of RIN was 4.7-fold higher than that of IRN, indicating IRN was more favorable to be metabolized than RIN in RLM.</p> <p>4. Data from chemical inhibition study demonstrated CYP3A was the predominant isoform involved in the metabolic elimination of both epimers, as well as the formation of M1-8.</p> <p>5. In conclusion, data revealed that due to the spatial configurations at C-7 position, RIN and IRN epimers possessed different hepatic metabolic pathways and elimination rates which were mainly mediated by CYP3A.</p>