Metabolism of metoprolol in the rat in vitro and in vivo.

1. Metoprolol was metabolized in rat liver microsomes in vitro by O-demethylation with subsequent oxidation and by aliphatic hydroxylation of the methoxy-ethyl substituent and by oxidative deamination of the propanolisopropylamine side-chain. The same routes of metabolism in the rat in vivo were revealed from urinary metabolites. Eight metabolites were identified by g.l.c.-mass spectrometry by comparison with synthetized reference compounds. 2. Metoprolol binds to cytochrome-P-450 eliciting a type I difference spectrum with KS = 23 +/- 2-0 muM. The apparent Michaelis-Menten constant Km = 39 +/- 4-0 muM and Vmax = 1-28 +/- 0-22 nmol/mg protein X min were not significantly affected by pre-treatment of the rats with metoprolol or phenobarbital. Metoprolol pre-treatment had no effect on the cytochrome-P-450 level in the microsomes nor on the rate of metabolism of four standard substrates. Phenobarbital increased the cytochrome P-450 as expected. 3. Four metabolites representing the three main routes of metabolism were quantitatively determined after metabolism with rat liver microsomes and compared with the urinary levels of the same compounds. The same major metabolites were found in vitro and in vivo. The total amount of metabolites was not influenced by pre-treatment with metoprolol or phenobarbital. The relative amounts of the three main metabolites were slightly affected by pre-treatment.