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 polymorphis m) and quinidine on (+/-)-metoprolol distribution parameters was inves tigated in 7 young male volunteers (4 extensive and 3 poor metaboliser s). (+/-) -Metoprolol tartrate 20 mg was administered as a 20 min infu sion 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 quinidin e sulphate b. d. as a slow-release tablet. No stereoselectivity was ap parent in either poor or extensive metabolizers. When (+/-)-metoprolol was administered alone the apparent volume of distribution at steady- state (V(ss)) 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 V(ss) in extensive metabolisers to value s comparable to those in poor metabolisers (3.50 and 3.18 l.kg-1, resp ectively), but had no significant effect in poor metabolisers (3.24 an d 3.42 l.kg-1, respectively). Estimation of V(ss) by noncompartmental analysis or assuming elimination exclusively from the peripheral compa rtment yielded similar, although somewhat higher, estimates. Despite t he small number of subjects, (+/-)-metoprolol distribution appeared to be different both in genetically and environmentally (quinidine)-dete rmined poor metabolisers, and quinidine inhibition was a good, reversi ble in vivo model of the genetic deficiency in handling (+/-)-metoprol ol. Differences both in first pass pulmonary elimination or in tissue binding are logically consistent with these observations, but the ampl itude of the effect exceeds expections from available biological evide nce on selective pulmonary metabolic activity and on specific tissue b inding sites.