Roles of amino acids in the food effect : metabolic and pharmacokinetic studies on propafenone and metoprolol
The bioavailability of some high hepatic first-pass drugs has been shown to increase substantially when they are orally administered with a protein-rich meal in humans. A change in hepatic metabolic capacity, induced by dietary amino acids (AAs), could be the cause of the food effect. The purpose of this work was to elucidate the possible mechanism by examining the effect of AAs on the kinetics and metabolism of two model drugs, propafenone and metoprolol, in the rat. By using HPLC/MS and MS/MS spectrometry, the metabolism of propafenone in the isolated, perfused rat liver was profiled. Hydroxylation in the terminal phenyl ring, which was not found in humans, was the major metabolic pathway. Additionally, a considerable proportion of the parent drug and the hydroxylated metabolites were subject to glucuronidation. Five glucuronide conjugates were structurally characterized, including two newly identified glucuronides. The study represented the first report on the metabolism of propafenone in the rat. A sensitive HPLC-UV method for the analysis of propafenone enantiomers, in rat liver perfusate was developed using GITC as a chiral derivatizing regent. Propafeonone enantiomers were highly bound to the hepatic tissue. Therefore, propafenone was not an appropriate model drug for studying the interaction in the rat. The interaction between metoprolol and AAs was studies in the isolated, perfused rat liver and the 'in vivo' rat. Rat livers were perfused in either antegrade or retrograde directions with metoprolol (5.48 [mu]M) in an erythrocyte-enriched medium. Amino acids caused a transient and reversible reduction in metoprolol metabolism. The magnitude of the reduction was dependant on the direction of perfusion, the hepatic oxygen delivery and the concentration of AAs. Moreover, a parallel study, in which rats were orally given metoprolol (10 mg/Kg) with either water or AA mixture, showed an increasing trend in metoprolol AUCoral and a significant prolongation in the t max of metabolites with AAs. The changes resembled the food effect observed in humans. In conclusion, these results strongly support that the inhibition of drug metabolism by dietary amino acids, probably caused by elevated consumption of oxygen in the hepatic tissues, is the significant mechanism contributing to the food effect.