Similar effect of oxidation deficiency (debrisoquine polymorphism) and quinidine on the apparent volume of distribution of (+/-)-metoprolol.
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.
Leemann
T D
TD
Department of Medicine, University Hospital, Geneva, Switzerland.
Devi
K P
KP
Dayer
P
P
D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology*
D001798:Blood Proteins; D008790:Metoprolol; D011802:Quinidine; D003647:Debrisoquin