The disposition of debrisoquine in hypertensive patients.

1 The disposition in urine of debrisoquine and its hydroxylated metabolites has been studied in subjects of the 'extensive metabolizer' (EM; n = 5) and 'poor metabolizer' (PM; n = 5) phenotypes. The 4-hydroxylation of debrisoquine by PM subjects following a 10 mg oral dose was capacity-limited and displayed significant dose-dependency over a range of 1-20 mg. In contrast, the EM subjects' ability to perform this metabolic oxidation did not deviate from first-order kinetics over a dose range of 10-40 mg. 2 The disposition of debrisoquine in plasma following a 10 mg oral dose has been studied in EM (n = 4) and PM (n = 3) subjects. Whilst PM subjects displayed significantly higher plasma levels of debrisoquine at all time points following 1 h post-dosing, and higher values for areas under the plasma concentration-time curve (EM: 105.6 + 7.0 ng ml-' h; PM: 371.4 + 22.4 ng ml-' h, 2P < 0.0001), neither debrisoquine plasma half-life (EM: 3.0 + 0.5 h; PM: 3.3 + 0.4 h) nor renal clearance of the drug (EM: 152.8 + 30.3 ml min-'; PM: 137 + 4.5 ml min-') displayed significant inter-phenotype differences. 3 The results of these investigations show that the phenotyping of individuals for debrisoquine oxidation status by means of a 'metabolic ratio' derived from a single 0-8 h urine sample has a sound kinetic basis. The kinetic differences between the two phenotypes would strongly suggest that the metabolic defect manifested in PM subjects is one of pre-systemic elimination capacity.

Section: Resultssupporting

confidence: 80%

Genetically determined oxidation capacity and the disposition of debrisoquine.

Sloan¹,

Lancaster²,

Shah³

et al. 1983

“…The clear bimodality found in the frequency distribution of the urinary M/HM ratio supports the findings of our panel study ratio its value may depend on urinary pH (Silas et al, 1978;Regardh & Johnsson, 1980). Nevertheless, in those countries where it is difficult to use debrisoquine for phenotyping purposes, metoprolol may be a suitable alternative.…”

supporting

confidence: 72%

Metoprolol metabolism and debrisoquine oxidation polymorphism‐ population and family studies.

McGourty¹,

Silas²,

Lennard³

et al. 1985

Self Cite

150

112

1 The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. 2 The loglo metoprolol to a-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P < 0.001).3 The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. 4 The major urinary metabolite of metoprolol metabolism was H117-04, the endproduct of O-dealkylation. The distribution of the log1o metoprolol to H117-04 (M/H117-04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P < 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. 5 These results indicate that both the a-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. 6 Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. 7 In a sub-group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post-exercise heart rate at 24 h after dosing.

“…Assuming that the absorption of debrisoquine is first order, then the hepatic concentration of the drug after a 1 mg dose must be well below saturation. The peak plasma concentration of debrisoquine after an oral dose of 10 mg is approximately 0.09 JIM (Silas et al, 1978(Silas et al, , 1980. The Km for debrisoquine 4-hydroxylase activity of human liver is 125 JIM (Boobis et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.

Speirs¹,

Murray²,

Boobis³

et al. 1986

Quinidine and its diastereoisomer quinine were tested in vitro for their effect on the 4-hydroxylation of debrisoquine, the O-deethylation of phenacetin and the l'-hydroxylation of bufuralol, by human liver microsomal samples; quinidine was studied for its effect on debrisoquine 4-hydroxylation in vivo. Quinidine was a potent inhibitor of the 4-hydroxylation of debrisoquine and the l'-hydroxylation of bufuralol, with IC50 values of 0.7 and 0.2 /M, being around 100 times more potent in this respect than quinine. Very much higher (1000-fold) levels of quinidine were required to inhibit the O-deethylation of phenacetin, being rather less potent in this than-quinine. Eight subjects were phenotyped for their debrisoquine oxidation status and found to be extensive metabolisers (EM). They were tested again after the co-administration of 50 mg of quinidine with the debrisoquine. The concomitant administration of quinidine increased the metabolic ratios (MRs) by a mean of 26-fold. The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested.