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.

Eleven subjects of previously determined debrisoquine oxidation phenotype status (extensive metabolizer [EM], n = 5; poor metabolizer [PM], n = 6) were studied for their ability to perform the aromatic 4-hydroxylation of phenytoin. The PM subjects studied were found to be slower metabolizers of phenytoin than EM subjects in terms of the metabolite formation rate constant (kfHPPH: EM, 0.030 +/- .007 hr-1; PM, 0.016 +/- 0.003 hr-1, 2p less than 0.001) and cumulative excretion of 4-hydroxyphenytoin (48 hr after dosing: EM, 52.8 +/- 10.7%; PM, 36.9 +/- 7.0%, 2p less than 0.01). It is concluded that the metabolic oxidation of phenytoin is influenced by the same DH and DL alleles, acting at the same locus, that regulate the hydroxylation of debrisoquine and that impaired metabolism of phenytoin may be expected to occur in about 9% of the population, being transmitted as an autosomal-recessive trait. It is suggested that debrisoquine oxidation phenotyping may have predictive value in guiding phenytoin dosage, particularly in those with impaired oxidation.

The influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation was studied by giving 500 mg antipyrine to 14 extensive and 10 poor metabolizers of debrisoquine. The pharmacokinetics of antipyrine were determined on the basis of the saliva concentration time curve and the cumulative urinary excretion of 4-hydroxyantipyrine, norañtipyrine, 3-hydroxymethyl-antipyrine, and 3-carboxyantipyrine was measured for 32 h following drug administration. Antipyrine elimination half-life, volume of distribution, and total clearance were almost equal for the two groups. Significant differences in the excretion of antipyrine metabolites were not observed, except for 3-hydroxymethyl-antipyrine which was excreted in poor metabolizers about 30% less than in extensive metabolizers (p < 0.01). However, this difference only reached borderline significance (p < 0.1) when clearance values for production of this metabolite were calculated. It is concluded that different species of the drug-oxidizing enzymes (cytochrome P-450 system) are involved in the metabolism of debrisoquine and antipyrine. Possibly the enzyme responsible for hydroxylating debrisoquine is partly involved in the formation of 3-hydroxymethyl-antipyrine.

1 The oxidative O-de-ethylation and aromatic 2-hydroxylation of phenacetin have been investigated in panels of extensive (EM, n = 13) and poor (PM, n = 10) metabolizers of debrisoquine. 2 The EM group excreted in the urine significantly more paracetamol (EM: 40.8 + 14.9% dose/0-8 h; PM: 29.2 + 8.7% dose/0-8 h, 2P < 0.05) and significantly less 2-hydroxylated metabolites (EM: 4.7 + 2.3% dose/0-8 h; PM: 9.7 + 3.5% dose/0-8 h, 2P < 0.005) than the PM group.3 Apparent first-order rate constants, calculated from pooled phenotype data, for overall elimination of phenacetin (k) and formation of paracetamol (km,1) were higher in the EM group (EM: k = 0.191 + 0.151 h-'; km, = 0.091 + 0.025 h-'; PM: k = 0.098 ± 0.035 h-', 2P < 0.05, km, = 0.052 + 0.019 h-', 2P < 0.05) than the PM group. The apparent first-order rate constant for 2-hydroxylation displayed no significant inter-phenotype differences. 4 Correlation analysis demonstrated that genetically determined oxidation status accounted for approximately 50% of the inter-individual variability in phenacetin disposition encountered in this study.

on a t.l.c. plate with methanol as solvent, and this produced a peak which corresponded to an EE sulphate marker. The second aliquot (100,l) was incubated with sulphatase (5 u) and saccharo-lactone (2 mg) in acetate-buffer (450 el; pH 5.0) and the third aliquot (100 isl) was incubated with ,B-glucuronidase (3500 u The rate of excretion of PHP in the EM subjects was faster than that in the PM individuals (Figure 1) and the difference was significant. Each Ghanaian subject displayed approximately constant rates of metabolite excretion, with no evidence of terminal linear decline at 48 h post-dosing. Such observations are consistent with a limited capacity for both phenotypes to form the major metabolite.The findings for Ghanaians are different from those previously observed for Caucasians as follows: (a)