Influence of the Genetically Controlled Deficiency in Debrisoquine Hydroxylation on Antipyrine Metabolite Formation

Abstract

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.

The Effects of Encainide versus Diltiazem on the Oxidative Metabolic Pathways of Antipyrine

“…Others have reported no difference in antipyrine clearance and half-life between extensive and poor metabolizers of debrisoquin, although there was a trend for lower urinary excretion of 3-OHM. 34 We noted no such trend in our PM subject.…”

Monogenic control of variations in antipyrine metabolite formation. New polymorphism of hepatic drug oxidation.

“…These statistically significant intraindividual correlations, together with closely similar frequencies for the genes that control each AP rate constant (Table II), suggested that a single genetic locus might control variations in all three AP rate constants. Though highly statistically significant (<0.001) because of the large number of subjects investigated The polymorphism in drug oxidation revealed using AP as substrate differs from the polymorphism of debrisoquine oxidation (26) since the debrisoquine phenotype of a subject appears unrelated to that subject's capacity to biotransform AP (27,28). Furthermore, the gene frequency of the debrisoquine polymorphism (P = 0.72 and q = 0.28 in a Caucasian population from the United Kingdom [29]) differs from the gene frequencies we observed in the AP polymorphism (Table II).…”

6 beta‐hydroxycortisol excretion in relation to polymorphic N‐oxidation of sparteine [letter]

“…However, the metabolism of antipyrine, which is quite frequently used as a 'model drug' in clinical pharmacological studies, is not related to sparteine or debrisoquine metabolism. Thus, antipyrine metabolism seems to be carried out by different enzyme systems (Bertilsson et al, 1980;Danhof et al, 1981;, submitted for publication).…”