MONOGENIC CONTROL OF VARIATIONS IN RATES OF ANTIPYRINE METABOLIC FORMATION IN MAN: A NEW PHARMACOGENETIC POLYMORPHIS

To investigate the role of genetic factors in controlling interindividual variations in antipyrine disposition, twin and family studies were performed in which rate constants for formation of the three main metabolites of antipyrine were measured. Eighty-three unrelated subjects, 40 twins and 61 members of thirteen 2-generation families, all between the ages of 18 and 55, received antipyrine (18 mg/kg) orally under carefully controlled environmental conditions. Antipyrine was readministered to all subjects two weeks later to establish the magnitude of intraindividual variability. High reproductibility of rate constants for formation of each main metabolite was observed. Relative contributions of genetic and environmental factors to 4- to 7-fold interindividual variations in rate constants for formation of the 3 main antipyrine metabolites were compared. Heritabilities based on the results of the twin studies measuring rate constants for formation of 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and N-demethylantipyrine were 0.88, 0.70, and 0.85, respectively. Pedigree analysis of the 13 families was consistant with a monogenic mode of transmission for interindividual variations in rate constants for formation of each antipyrine metabolite. Family members were phenotyped based on their respective positions within distribution curves comprising values for rate constants for formation of each antipyrine metabolite in 83 unrelated subjects. These curves revealed trimodality in the distribution of values for each rate constant for metabolite formation which was confirmed by probit regression analysis. Gene frequencies measured for each rate constant for antipyrine metabolite formation were found to be in Hardy-Weinberg equilibrium. Although the distribution curve of the overall antipyrine elimination rate constant was also trimodal, 4 of the 13 pedigrees were incompatible with a monogenic mode of transmission and because a monogenic hypothesis for the control of interindividual variations in rate constants of antipyrine dimination had to be rejected. Similar gene frequencies (p = 0.80, 0.89, and 0.90) and statistically significant correlations among rate constants for formation of antipyrine metabolites, raises the question of how many distinct genetic loci are involved. Diurnal variations were noted in urinary metabolite output. The cause of these rhythmic changes in metabolite elimination is unclear.