The effect of ritonavir on the pharmacokinetics of clonidine in vivo and in vitro.

Abstract

This project aims to explore the repercussions of ritonavir on both the drug kinetics of clonidine in rats and clonidine metabolism in liver micro somes. Eighteen healthy male laboratory rats were haphazardly placed into groups: Group A, the control, Group B, got 20mg/kg ritonavir and Group C, got 180 mg/kg ritonavir. Ritonavir was administered to the rats by oral gavage and 30 minutes later, clonidine at 0.25mg/kg was administered for once. Moreover, rat and human liver micro somes, along with recombinant human CYP2D6*1, were used to study the inhibition effect of ritonavir on clonidine in vitro. The concentrations of clonidine and its metabolite were determined by the UPLC-MS/MS. The area under the curve (AUC) of clonidine increased (P<0.01) and clearance (CL) decreased significantly (P<0.01), after co-administration with 180mg/kg ritonavir. The half-maximal inhibitory concentration (IC₅₀) of ritonavir was 11.48μmol/L in rat liver micro somes, 3.52μmol/L in human liver micro somes and 18.04μmol/L in CYP2D6*1. Our findings demonstrate that ritonavir exhibited an inhibitory effect on clonidine metabolism in vitro and in vivo. It suggests that concurrent use of clonidine with ritonavir required close monitoring of the clonidine plasma concentration to alert drug adverse reactions.