Impact of Hepatic-Intestinal First-Pass Effect on the Bioavailability of Schizandrin in Rats

  OBJECTIVES  The pharmacokinetic analysis of schizandrin in rats were performed to investigate the potential impact of intestinal-hepatic first-pass effect on the low bioavailability of schizandrin from Schizandra sinensis Baill.

  METHODS  Firstly, the pharmacokinetic assay was carried out in rats following intravenous (i.v) or intragastric (i.g) administration at different dose levels (10, 20, 50 mg · kg^-1). Secondly, the jugular vein or pyloric vein cannulated rats model was established to study the specific role of intestine and liver on the schizandrin.

  RESULTS  Schizandrin was rapidly absorbed (T_max, 0.37, 0.44, 0.33 h), quickly eliminated with short mean resident time (MRT_last, 1.74, 1.65, 1.27 h) and low bioavailability (12.0%, 11.0%, 9.35%) in conscious rats treated with i.g administration 10, 20, 50 mg · kg^-1 of schizandrin. The systemic exposure to schizandrin was comparable (AUC_0-t, 467.98 vs 469.03 h · ng · mL^-1) after i.g or intraduodenal (i.d) puncture administration at 20 mg · kg^-1. This indicated the gastric effect to the metabolism of schizandrin was minor. Following i.d administration of schizandrin at 20 mg · kg^-1, the pre-systemic exposure to schizandrin in pyloric vein was higher than that in jugular vein (AUC_0-t, 1 648.08 vs 469.03 h · ng · mL^-1). The calculated intestinal metabolism was estimated at 78.47%; After intravenous administration via portal vein at 10 mg · kg^-1, the systemic exposure in jugular vein was a bit lower than that following intravenous via jugular vein at identical dose (AUC_0-t, 1 960.22 vs 2 547.79 h · ng · mL^-1), indicating the hepatic metabolism occupied 23.06%. Comprehensive consideration of intestinal (F_a × F_g, 21.53%) and hepatic (F_h, 76.94%) availability, the total bioavailability was estimated as 16.57% in cannulated rats, which was close to the value (18.33%) calculated from the i.g and i.v administration in anaesthetic rats. In the intestinal and hepatic microsomes incubation system, schizandrin was extensively degraded in the presence of NADPH.

  CONCLUSIONS  The intestinal-hepatic first-pass effect largely determines the bioavailability of schizandrin, while the intestine contributes in a larger extent.