Preclinical study of a potent P-glycoprotein and cytochrome P450 enzyme inducer rifampicin changing pharmacokinetic parameters of risperidone and its metabolite, 9-hydroxyrisperidone, using a rat model

The objective of the present investigation is to examine the effects of rifampicin, which is a P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 inducer, on the pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, in rats. To determine the plasma levels of risperidone and 9-hydroxyrisperidone in rats, a high performance liquid chromatographic method was developed using a liquid-liquid acid back extraction. After pretreated with rifampicin (600 mg/kg) for 6 days, the mean C_max and AUC_0-10 values of risperidone were significantly decreased and the Cl_t of the drug was significantly increased compared with control (p < 0.01, <0.05, and <0.05, respectively). The C_max and AUC_0-424 of 9-hydroxyrisperidone were also significantly decreased compared with control (p < 0.01, respectively). Thus, the relative bioavailability of risperidone and 9-hydroxyrisperidone once pretreated with rifampicin (600 mg/kg) was 42.5 and 32.5 %, respectively. The exposure of rifampicin significantly decreased oral bioavailability and affected the pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, by the induction of P-gp and CYP3A4 as well.