Human intestine and liver microsomal metabolic differences between C19-diester and monoester diterpenoid alkaloids from the roots of Aconitum carmichaelii Debx.

The roots of Aconitum carmichaelii Debx. show excellent effects against rheumatism and cardiovascular diseases, but the effective compounds, C-19-diester and monoester diterpenoid alkaloids (DDA5 and MDAs) are toxic for their narrow therapeutic windows. It is noteworthy to investigate intestinal metabolism of these toxic compounds mainly by oral administration, because gut also express drug-metabolizing enzymes as well as liver. This study initially focused on phase I and phase II metabolism of DDAs (including aconitine, mesaconitine and hypaconitine) and MDAs (including benzoylaconine, benzoylmesaconine and benzoylhypaconine) in human intestine microsomes (HIM), with comparison of metabolism in human liver microsomes (HLM). CYP3A in HIM mainly catalyzed phase I metabolism of DDAs and MDAs, with polarity increased. The intestinal metabolic profiles of DDAs were more various than MDAs. No glucuronide metabolites were detected, which was in agreement with HLM metabolism. The results showed that gut played an important role in detoxification of DDAs and MDAs by oral administration. Moreover, eight new metabolites from DDAs were identified in microsomes incubations by UPLC-Q-TOF-HRMS/MS. Our findings provided reference to the detoxification of DDAs and MDAs in the intestine in vivo and supplemented the phase I metabolic pathways for DDAs.