Sources of interindividual variations in acetaminophen and antipyrine metabolism

Our goal was to compare and contrast in the same normal twins the relative contribution of genetic and environmental factors to large interindividual variations in the metabolism of acetaminophen (APAP) and antipyrine. These drugs were selected because they are biotransformed by different mechanisms. A single oral dose of APAP (10 mg/kg) was given to six sets of monozygotic (MZ) and six sets of dizygotic (DZ) twins. All were normal, nonsmoking, nonmedicated, and male. Among these 24 subjects, there were 300% interindividual variations in rate constants for formation of the sulfate and glucuronide conjugates, as well as in the overall rate constant for APAP elimination. Intratwin variations for each measurement were as large within MZ as within DZ twinships, suggesting that predominantly environmental rather than genetic factors maintained interindividual variations. Two other observations support this conclusion: Intraindividual variations were frequently as large as interindividual variations, and regardless of zygosity for twins living together, intratwin correlation coefficients were almost twice those of twins living apart. Quite different results were obtained when these twins received antipyrine. After a single oral dose of antipyrine (18 mg/kg), 500% interindividual variations in rate constants for formation of the three main oxidative metabolites of antipyrine appeared to be mainly under genetic control. Also for antipyrine and its principal metabolites, intraindividual variations were much smaller than interindividual variations. In contrast to the results with APAP, regardless of zygosity, intratwin correlation coefficients for antipyrine were similar for twins living apart and twins living together. This comparison between APAP and antipyrine metabolism in the same carefully selected normal twins under apparently uniform environmental conditions reveals that interindividual variations in APAP metabolism arise from certain unidentified environmental factors, whereas genetic factors cause the large interindividual variations that occur in antipyrine disposition.