Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers

Abstract

The hypothesis that variability in metoprolol metabolism stereoselectivity is related to debrisoquin oxidation phenotype was tested in six extensive (EM) and six poor (PM) debrisoquin metabolizers. In EM, plasma AUCs for (S)-metoprolol were 35% higher than for (R)-metoprolol, whereas in PM, AUCs for (S)-metoprolol were lower than for (R)-metoprolol. AUCs for total metoprolol correlated with the ratio of (S)- to (R)-metoprolol AUC. The renal clearance of metoprolol was also stereoselective but to the same extent in both EM and PM. Findings suggest that the enzyme system responsible for polymorphic oxidation of the debrisoquin-type is stereoselective. The relation between log total metoprolol plasma concentration and response (beta-blockade) was shifted to the right in PM relative to EM, which is compatible with a difference in pharmacologic activity of metoprolol enantiomers. Kinetic predictions based on total drug measurements will tend to overestimate dynamic differences between EM and PM, but the magnitude of the error is relatively small, and, in absolute terms, there is a large difference in pharmacologic activity between the phenotypes (beta-blockade at 24 hr: EM = 5.3 +/- 5.6%; PM = 18.9 +/- 3.8%).

Enantioselective disposition of ofloxacin in humans

“…Recently, progress in the development of analytical methods for the efficient resolution of enantiomers has facilitated studies of the differences in the pharmacological properties of the enantiomers of many chiral agents, and it has been shown that such differences can originate from stereoselectivity in their absorption (22), distribution (1,26), receptor binding (23), metabolism (17,18) and/or excretion (10). Among the quinolone antibacterial agents there are many drugs, such as lomefloxacin, sparfloxacin, and OFLX, which possess an asymmetric carbon in their chemical structures.…”

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.…”

β-Adrenergic Receptor Blockade in Chronic Heart Failure

“…Metoprolol also undergoes stereoselective metabolism by CYP2D6 but in favor of the R isomer. 110 Stereoselective metabolism of metoprolol results in only a small difference in S/R plasma levels (1.35-fold higher S/R ratios in extensive debrisoquin metabolizers, reduced to an S/R ratio of Ͻ1 in poor metabolizers). 110 However, in poor metabolizers taking metoprolol, the lower S/R ratio leads to less ␤-blockade relative to plasma levels, 111 which tends to cancel the effect of the increased plasma levels of both isomers that is related to the lower oxidation rate.…”

“…110 Stereoselective metabolism of metoprolol results in only a small difference in S/R plasma levels (1.35-fold higher S/R ratios in extensive debrisoquin metabolizers, reduced to an S/R ratio of Ͻ1 in poor metabolizers). 110 However, in poor metabolizers taking metoprolol, the lower S/R ratio leads to less ␤-blockade relative to plasma levels, 111 which tends to cancel the effect of the increased plasma levels of both isomers that is related to the lower oxidation rate. Clinically important stereoselective metabolism does not occur for bisoprolol, 112 nebivolol, 113 or bucindolol (D. Ward, personal communication, 1999).…”