Evodiamine decreased the systemic exposure of pravastatin in non-alcoholic steatohepatitis rats due to the up-regulation of hepatic OATPs

Abstract

Context Patients with non-alcoholic steatohepatitis (NASH) may have a simultaneous intake of pravastatin and evodiamine-containing herbs. Objective The effect of evodiamine on the pharmacokinetics of pravastatin and its potential mechanisms were investigated in NASH rats. Materials and methods The NASH model was conducted with feeding a methionine choline-deficient (MCD) diet for 8 weeks. Sprague-Dawley rats were randomised equally (n = 6) into NASH group, evodiamine group (10 mg/kg), pravastatin group (10 mg/kg), and evodiamine (10 mg/kg) + pravastatin (10 mg/kg) group. Normal control rats were fed a standard diet. Effects of evodiamine on the pharmacokinetics, distribution, and uptake of pravastatin were investigated. Results Evodiamine decreased Cmax (159.43 ± 26.63 vs. 125.61 ± 22.17 μg/L), AUC0-t (18.17 ± 2.52 vs. 14.91 ± 2.03 mg/min/L) and AUC0-∞ (22.99 ± 2.62 vs. 19.50 ± 2.31 mg/min/L) of orally administered pravastatin in NASH rats, but had no significant effect in normal rats. Evodiamine enhanced the uptake (from 154.85 ± 23.17 to 198.48 ± 26.31 pmol/mg protein) and distribution (from 736.61 ± 108.07 to 911.89 ± 124.64 ng/g tissue) of pravastatin in NASH rat liver. The expression of Oatp1a1, Oatp1a4, and Oatp1b2 was up-regulated 1.48-, 1.38-, and 1.51-fold by evodiamine. Evodiamine decreased the levels of IL-1β, IL-6, and TNF-α by 27.82%, 24.76%, and 29.72% in NASH rats, respectively. Discussion and conclusions Evodiamine decreased the systemic exposure of pravastatin by up-regulating the expression of OATPs. These results provide a reference for further validation of this interaction in humans.

Keywords

• drug-drug interaction
• pharmacokinetics
• hepatic uptake
• organic anion transporting polypeptide