PMID: 9172945Mar 1, 1997Paper

Inhibition of metoprolol metabolism by amino acids in perfused rat livers. Insights into the food effect?

Drug Metabolism and Disposition : the Biological Fate of Chemicals
B O Wang, H A Semple

Abstract

A mixture of amino acids inhibits propranolol metabolism in perfused rat livers. To obtain mechanistic information about the interaction, a related but less tissue-bound drug, metoprolol, was used to determine Vmax and K(M) for parent drug and two metabolites in the presence and absence of amino acids. Six groups of 4 livers from 24 male Sprague-Dawley rats were perfused in the single-pass mode at 3 ml/min/g liver for 130 min with oxygenated buffer containing 3.74, 4.49, 5.61, 7.48, 18.7, or 44.9 microM metoprolol. From 50 to 90 min, a balanced amino acid mixture was included in the buffer. Samples of liver effluent taken every 5 min were analyzed by HPLC for metoprolol and two metabolites, alpha-hydroxymetoprolol and O-demethylmetoprolol. Steady-state concentrations of drug determined before, during, and after amino acids were used to determine Vmax and apparent K(M) values by nonlinear curve-fitting under each condition. Amino acids reversibly reduced the Vmax values of metoprolol and both metabolites by approximately 50% without significantly affecting apparent K(M) values. As a result, large increases in availability occurred, especially at low metoprolol inlet concentrations (> 90%). Amino acids also increased oxygen consu...Continue Reading

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