The influence of drug pre-exposure on first-pass metabolism of tacrine.

摘要

The nonlinear pharmacokinetic behavior of tacrine has been observed both in humans and laboratory animals. The objective of the current studies is to investigate the underlying mechanism of tacrine nonlinearity.; Two consecutive intraduodenal doses of tacrine were given to rats. The results indicate that tacrine pre-exposure changes the kinetics of a 2 nd identical dose. The AUC for tacrine doubled after the 2 nd dose and no change was observed in the terminal elimination rate constant, which suggests that the bioavailability of tacrine increased with the 2nd dose. Since tacrine is eliminated from the body mainly by metabolism catalyzed by CYP1A, it is conceivable that tacrine pre-exposure inhibits the enzyme activity. The behavior of 2HT, a major metabolite, was very similar to tacrine, with a 2nd/1st AUC ratio averaging 1.44. On the contrary, the 2nd dose AUC for 1HT, another metabolite, was only 75% of the 1st dose AUC, indicating that the 1-hydroxylation pathway was suppressed by tacrine pre-exposure.; In the in vitro enzyme inhibition studies, THA inactivated CYP1A2 in a time- and concentration-dependent manner. The inactivation was also NADPH dependent and not affected by the trapping agent, glutathione. All these results suggest that THA may be a mechanism-based inhibitor of CYP1A2. It was also found that THA inhibited CYP1A1 activity in a concentration-dependent but time-independent manner, suggesting that this inhibition process was reversible and equilibrium was achieved very quickly.; Tacrine metabolism catalyzed by recombinant CYP1A1 and CYP1A2 was also carried out. A modified Michaelis-Menten equation involving mechanism-based inhibition was derived and used to analyze the data describing 1HT formation. Reasonable parameter fits were obtained indicating that this equation is suitable to describe metabolism data when the substrate is a mechanism-based inhibitor of the enzyme.; THA, 1HT, & 2HT kinetics were simulated using a hybrid physiologically-based model under the assumptions of saturable metabolism in gut mucosa and mechanism-based inactivation in liver. Results from the simulations are in good agreement with the observed data. The same model successfully predicted the PK profiles of THA, 1HT, and 2HT after two consecutive intravenous doses.