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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.

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1. After oral administration of alprenolol to rat, 12 metabolites were isolated and characterized as trifluoroacetyl, trimethylsilyl and n-butylboronate derivatives, using a g.l.c.-mass spectrometry-computer system. Fragmentation pathways of derivatives in the mass-spectrometric analysis are discussed. 2. Metabolic reactions involved are oxidative degradation of the propanolisopropylamine side-chain, aromatic hydroxylation, oxidation of the allyl group, and conjugation. A method for direct analysis of epoxide functions in the allyl group is described. 3. In comparison with metabolism of alprenolol in vitro, more polar metabolites are formed in vivo but the same principal metabolic pathways are valid. Structural features for biliary excretion are discussed.

The metabolic pathways of alprenolol have been investigated in man and the dog, using an ion doublet technique of deuterium labelling combined with gas chromatography mass spectrometry. The drug is eliminated mainly by aromatic hydroxylation and glucuronidation. Specific analytical methods are applied to demonstrate that allylic oxidation and oxidative deamination are quantitatively of minor importance. The mechanism for oxidative deamination via an intermediary aldehyde could be elucidated by using the deuterium labelled compound. A method for characterization of 4-hydroxy-alprenolol glucuronides based on formation of stable derivatives and the following enzymatic hydrolysis is described. This approach has a general applicability to hydroxylated metabolites from compounds with an aminopropanol structure common for beta-adrenoceptor antagonists, for example. The metabolic routes for alprenolol in man and the dog are almost identical and in man more than 95% of a given dose can be accounted for.