Metoprolol oxidative metabolism

Metoprolol is a (3-blocker that has been proposed as a pharmacokinetic alternative to debrisoquine in countries where it is difficult to use debrisoquine. Metoprolol is metabolized to desmethylmetroprolol and a-hydroxymetoprolol by CYP2D6 (124). The a-hydroxymetoprolol metabolite has been shown to be bimodally distributed and to correlate with the debrisoquine oxidation phenotype (125). Again, metoprolol has been used primarily to distinguish between CYP2D6 EMs and PMs. However, in African populations, the metoprolol metabolic ratio failed to predict the PMs of debrisoquine (126). These studies would suggest that in some ethnic groups metoprolol may not be a suitable probe. 

Belpaire FM, Wijnant P, Temmerman A, et al. The oxidative metabolism of metoprolol in human liver microsomes-inhibition by the selective serotonin reuptake inhibitors. Eur J Clin Pharmacol 1998 54 261-264. 

Metoprolol oxidation cosegregates with debrisoquine hydroxylation, and debrisoquine phenotype significantly affects the stereoselective metabolism of the drug [38]. The influence of debrisoquine hydroxylation phenotype on the pharmacokinetics and pharmacodynamics of both propranolol and metoprolol is described later in this chapter. 

Kim, M. Shen, D.D. Eddy, A.C. Nelson, W.L. Roskos, L.K. Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes. Drug Metab. Dispos. 1993, 21, 309-317. 

Cinnarizine, l-(diphenylmethyl)-4-(3-phenyl-2-propenyO-piperazine is a selective calcium entry blocker, and is extensively used in the treatment of cerebral and peripheral insufficiency (Godfraind et al. 1982, Singh 1986). Its oxidative metabolism to l-(diphenylmethyl)piperazine (M-1), l-(diphenyl-methyl)-4-[3-(4 -hydroxyphenyl)-2-propenyl]-piper-azine (M-2b benzophenone (M-3) and l-[4 -hydro-xyphenyl)-phenylmethyl] - 4 -(3-phenyl-2-propenyl) piperazine (M-4) in rat liver microsomes required NADPH, and was inhibited by carbon monoxide and SKF 525-A, typical inhibitors of P450 (Kariya et al. 1992). Only M-2 formation was suppressed by sparteine or metoprolol, and was significantly lower in female Dark Agouti rats than in Wistar rats of both sexes. 

Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF. Oxidation phenotype—a major determinant of metoprolol metabolism and response. N Engl J Med 1982 307 1558-1560. 

McGourty JC, Silas JH, Lennard MS, et al. Metoprolol metabolism and debrisoquine oxidation polymorphism-population and family studies. Br J Clin Pharmacol 1985 20 555-566. 

Iyun AO, Lennard MS, Tucker GT, et al. Metoprolol and debrisoquin metabolism in Nigerians lack of evidence for polymorphic oxidation. Clin Pharmacol Ther 1986 40 387-394. 

Horai Y, Taga J, Ishizaki T, et al. Correlations among the metabolic ratios of three test probes (metoprolol, debrisoquine and sparteine) for genetically determined oxidation polymorphism in a Japanese population. Br J Clin Pharmacol 1990 29 111-115. 

Scheme 8.5 Metabolism of metoprolol, 28, is thought to involve "...rapid cleavage of the methoxyethyl chain at the methoxy group to afford a 2-phenylethanol derivative" [92] which is subsequently oxidized to the corresponding phenylacetic acid derivative, 28a [97]. Another metabolite is produced by oxidation of the...

The oxidative clearance of the lipophilic drugs, metoprolol, timolol, and bufuralol, is influenced by the debri-soquine hydroxylation gene locus, resulting in polymorphic metabolism (233). This might result in an... 

Most beta-blockers undergo extensive oxidation (329). There have been anecdotal reports of high plasma concentrations of some beta-blockers in poor metabolizers of debrisoquine, and controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics, and some of the pharmacological effects of metoprolol, bufuralol, timolol, and bopindolol. The poor metabolizer phenotjrpe is associated with increased plasma drug concentrations, a prolonged half-life, and more intense and sustained beta-blockade. There are also phenotypic differences in the pharmacokinetics of the enantiomers of metoprolol and bufuralol. 

Metoprolol (53) is cleared principally by hepatic metabolism and is only 50%bioavailable because of extensive first-pass metabolism. The major metabolite (65%)is the carboxylic acid (95), produced by (2yP2D6 (9-demethyl-ation followed by further oxidation (32-34). Benzylic oxidation CYP2D6 forms an active metabolite (96), which retains beta-blocking activity (35). The N-dealkylated product is a minor metabolite. 

Metoprolol is another beta-blocker that is predominantly eliminated by hepatic metabolism [38]. In humans, metoprolol is eliminated by several oxidation pathways, including benzylic hydroxylation (a-hydroxylation), which results in an active metabolite and accounts for 10% of the dose [39]. This pathway is stereoselective for S(—)-metoprolol. The major metabolic pathway, however, is O-demethylation and further oxidation to a carboxylic acid metabolite that accounts for 65% of the dose [38]. O-demethylation favors R(- -)-metoprolol [39] and facilitates the stereoselectivity observed in the plasma concentrations of metoprolol. A third metabolic pathway (N-dealkylation) accounts for < 10% of the dose in humans [39]. 

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