Pharmacokinetics of a chemoprotective agent, 2-(allylthio)pyrazine, after intravenous and oral administration to rats: hepatic and gastric first-pass effects.

摘要

Pharmacokinetic parameters of 2-(allylthio)pyrazine (2-AP) were evaluated after i.v. administration of the drug (10, 20, 50, and 100 mg/kg body weight) and oral administration of the drug (10, 50, and 100 mg/kg body weight) to rats. The hepatic, gastric, and intestinal first-pass effects of 2-AP were also measured after i.v., intraportal, intraduodenal, and oral administration of the drug (10 and 50 mg/kg body weight) to rats. After i.v. administration, the pharmacokinetic parameters of 2-AP were dose-independent at the dose ranges studied. However, after oral administration, the dosenormalized total area under the plasma concentration-time curve from time zero to time infinity values (43.5, 125, and 205 microg min/ml, based on 10 mg/kg body weight) increased significantly with increasing doses. The extent of absolute oral bioavailability (F) values also increased with increasing oral doses; the values were 19. 6, 56.7, and 93.6% for 10, 50, and 100 mg/kg body weight, respectively. The oral data above could be due to saturable hepatic, gastric, and/or intestinal first-pass effects. This was proved by saturable gastric first-pass effect (the significant area under the plasma concentration-time curve from time zero to time infinity difference between oral and intraduodenal administration of 2-AP); the values were 62.6 and 26.6% at 2-AP doses of 10 and 50 mg/kg body weight, respectively. Approximately 20% of oral dose was eliminated by liver (hepatic first-pass effect) for both oral doses of 10 and 50 mg/kg body weight. However, the first-pass effects of 2-AP in the intestine, heart, and lung were almost negligible. The low F value after oral administration of 2-AP at low dose (10 mg/kg body weight) was mainly due to gastric first-pass effect in rats.