Similar effect of oxidation deficiency (debrisoquine polymorphism) and quinidine on the apparent volume of distribution of (�)-metoprolol

Abstract

The influence of phenotype (debrisoquine type of oxidation polymorphism) and quinidine on (+/-)-metoprolol distribution parameters was investigated in 7 young male volunteers (4 extensive and 3 poor metabolisers). (+/-)-Metoprolol tartrate 20 mg was administered as a 20 min infusion i) alone, ii) 12 h after an oral 50 mg quinidine sulphate capsule, and iii) on the last day of 3 days of treatment with 250 mg quinidine sulphate b.d. as a slow-release tablet. No stereoselectivity was apparent in either poor or extensive metabolizers. When (+/-)-metoprolol was administered alone the apparent volume of distribution at steady-state (Vss) was higher in extensive than in poor metabolisers (4.84 vs 2.83 l.kg-1, respectively). Pre-treatment with low or multiple high doses of quinidine decreased Vss in extensive metabolisers to values comparable to those in poor metabolisers (3.50 and 3.18 l.kg-1, respectively), but had no significant effect in poor metabolisers (3.24 and 3.42 l.kg-1, respectively). Estimation of Vss by noncompartmental analysis or assuming elimination exclusively from the peripheral compartment yielded similar, although somewhat higher, estimates. Despite the small number of subjects, (+/-)-metoprolol distribution appeared to be different both in genetically and environmentally (quinidine)-determined poor metabolisers, and quinidine inhibition was a good, reversible in vivo model of the genetic deficiency in handling (+/-)-metoprolol. Differences both in first pass pulmonary elimination or in tissue binding are logically consistent with these observations, but the amplitude of the effect exceeds expectations from available biological evidence on selective pulmonary metabolic activity and on specific tissue binding sites.

Enantioselectivity in the steady-state pharmacokinetics of metoprolol in hypertensive patients

“…We used the debrisoquine metabolic ratio % of dose excreted as debrisoquine/% of dose excreted as 4-hydroxydebrisoquine less than 12.6 to classify our subjects as extensive metabolizers (EM), considering that 70-80% of metoprolol metabolism is mediated via the genetically determined activity of CYP2D6 and that poor metabolizers (PM) show loss of stereoselective metabolism of both enantiomers of metoprolol. [9][10][11][12] In our study, debrisoquine metabolic ratios varied widely among the hypertensive patients, ranging from 0.28 to 6.56.…”

“…Although previous studies have shown the bioavailability of racemic metoprolol to be 38 ± 14%, the pharmacokinetic parameters depending on bioavailability such as distribution volume and clearance are calculated in a more precise manner as apparent parameters, i.e., Cl T /f and V d /f, since there are no data about the bioavailability of the individual enantiomers. 11 permits us to suggest that the route of administration is a factor influencing enantioselectivity. Metoprolol is a drug with medium to high hepatic extraction and therefore its hepatic clearance depends much more on hepatic blood flow than on intrinsic clearance when administered intravascularly.…”

“…8 The route of administration is also relevant in the manifestation of enantioselectivity. Leeman et al (1993) 11 did not observe enantioselectivity in the kinetics of intravenous metoprolol in healthy volunteers.…”

“…Quinidine is a potent inhibitor of metoprolol metabolism in extensive metabolizer volunteers. 10,11 Diltiazem and propafenone reduce the clearance of metoprolol in healthy volunteers. 19,21 Co-administration of metoprolol and felodipine results in increased maximum plasma concentration (C max ) and area under the metoprolol plasma concentration versus time curve (AUC).…”

Influência do etilbenzeno na farmacocinética enantiosseletiva do metoprolol em ratos

“…Apesar da completa absorção gastrintestinal, em razão da alta eliminação pré-sistêmica somente 50% da dose atinge a circulação sob a forma inalterada (BORG et al, 1975;LEEMANN;DEVI;DAYER, 1993) A formação do metabólito α-hidroximetoprolol é dependente da atividade geneticamente determinada do CYP2D6 e relaciona-se com o fenótipo de oxidação tipo debrisoquina/esparteína (LENNARD; TUCKER; WOODS, 1986).…”