The inhibitory effects of shikonin and β,β-dimethylacrylshikonin on tramadol metabolism in vitro and in vivo

Abstract

Abstract Objectives The objective of this study was to investigate the possible interaction of shikonin and β,β-dimethylacrylshikonin (DSK) with tramadol. Methods Human liver microsome (HLM) and rat liver microsome (RLM) incubation experiments were carried out to assess the half-maximal inhibitory concentration (IC50) and inhibitory mechanism of shikonin and DSK on tramadol metabolism in vitro. And pharmacokinetics experiments containing low and high doses of shikonin and DSK were performed to confirm the inhibitory effects on tramadol metabolism in vivo. Key findings The IC50 of shikonin on tramadol metabolism was 5.66 ± 1.2 μmol/l in HLM and 3.35 ± 1.1 μmol/l in RLM, while that of DSK on tramadol metabolism was 14.33 ± 1.1 μmol/l in HLM and 8.24 ± 1.26 μmol/l in RLM. Moreover, shikonin and DSK showed non-competitive inhibition of the cytochrome P450 enzyme in both HLM and RLM. Oral administration of 10 and 30 mg/kg shikonin inhibited tramadol metabolism in a dose-dependent manner. Furthermore, a dose of 30 mg/kg DSK inhibited the metabolism of tramadol in rats, while the lower dose of 10 mg/kg showed no inhibitory effect. Conclusions The results of this study suggest that shikonin and DSK can inhibit tramadol metabolism both in vitro and in vivo.