In vitro hepatic biotransformation of cepharanthine, a bisbenzylisoquinoline alkaloid

Cepharanthine is a major biscoclaurine (bisbenzylisoquinoline) alkaloid isolated from the tuber of Stephania rotunda Lour., a Cambodian creeper belonging to the family of Menispermaceae [1]. Cepharanthine exerts various biological effects including antiplasmodial [1], cytotoxic [2] and antioxidant [3] activies, but the metabolism of this compound has not been elucidated to date. The aim of the present investigation was to study in vitro phase I metabolism of cepharanthine using liver microsomes from different species. Incubation of cepharanthine with human liver microsomes led to the formation of one major metabolite, detected by HPLC-DAD. Enzyme kinetics were investigated with pooled human liver microsomes. The apparent Michaelis-Menten constants for the human major metabolite were Km=37.7µM and Vm=22.7 nmol/mg/h. We conducted inter-individual variability study using 20 different human liver microsomes. Results showed marked inter-individual differences in human cepharanthine metabolism. In addition, the biotransformation of this alkaloid was investigated using liver microsomes from different animal species (rats, mice, rabbits, guinea-pigs). Experiments showed important inter-species variability of cepharanthine metabolism