Defective metabolism of metoprolol in poor hydroxylators of debrisoquine.

Abstract

Eight healthy volunteers received oral metoprolol 200 mg once daily for a week. The AUC, half-life and duration of B-adrenoceptor blockade on day 7 was much greater in two subjects than in the remaining six. This suggested that the metabolism of metoprolol was impaired in two and the effect was therefore prolonged. Subsequent testing of oxidation phenotype with oral debrisoquine showed that the subjects with high metoprolol availability were also poor hydroxylators of debrisoquine. The urinary debrisoquine/4-hydroxydebrisoquine ratio was highly correlated with metoprolol AUC, half-life and ,3-adrenoceptor blockade at 24 h. Thus patients with a genetic defect in drug oxidation, when treated with metoprolol, are likely to have high plasma concentrations and a prolonged effect.

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

“…CYP2D6 catalyzes O-demethylation and, even more specifically, a-hydroxylation of the drug. 39 Metabolism by CYP2D6 showed a slight preference for the (R)-enantiomer over the pharmacologically active (S)-enantiomer 40 but in both enantiomers, there is a substantial difference between CYP2D6 EMs and PMs. 41,42 Not only metoprolol plasma concentrations but also the effects on heart rate correlated significantly with CYP2D6 metabolic phenotype.…”

“…41,42 Not only metoprolol plasma concentrations but also the effects on heart rate correlated significantly with CYP2D6 metabolic phenotype. 39,43 Kirchheiner et al 44 described the effects of CYP2D6 genotype on pharmacokinetics of metoprolol and heart rate. In UMs carrying the CYP2D6 gene duplication, total clearance of metoprolol was about 100% higher compared with EMs (367 versus 168 l/h).…”

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

“…Population studies also suggest that the metabolism of these drugs is under common genetic control (Lennard et al, 1982a(Lennard et al, , b, 1983aDayer et al, 1982Dayer et al, , 1983. Furthermore, there is evidence that metoprolol produces more intense and more prolonged ,8-adrenoceptor blockade in poor metabolisers of debrisoquine than in extensive metabolisers (Lennard et al, 1982b).…”

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

“…Early studies showed that patients who have no functional alleles of CYP2D6 (poor metabolisers (PMs)), who comprise approximately 7% of the Caucasian population, 5 achieve 3-to 6-fold higher concentrations of racemic metoprolol than extensive metabolisers (EMs) after a single-dose 6,7 and with repeated dosing. [8][9][10][11] Stereoselective metabolism exists, with the inactive R-enantiomer more dependent on CYP2D6 for metabolism, as indicated by an S/R concentration ratio of B1.1 and 1.7 in PMs versus EMs, respectively. 12 Additionally, studies in healthy volunteers indicate that PMs experience enhanced or prolonged b-blockade compared with EM subjects.…”