Sources of interindividual variations in acetaminophen and antipyrine metabolism

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Abstract
The relative contribution of genetic and environmental factors to large interindividual variations in acetaminophen (APAP) and antipyrine metabolism was compared and contrasted in the same normal twins. These drugs were selected because they are biotransformed by different mechanisms. A single oral APAP (10 mg/kg) dose was given to 6 sets of monozygotic (MZ) and 6 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 sulfate and glucuronide conjugate formation, as well as in the overall APAP elimination rate constant. 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. Other obsrevations (2) 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 diffrent results were obtained when these twins received antipyrine. After a single oral antipyrine (18 mg/kg) dose, 500% interindividual variations in rate constants for formation of the 3 main antipyrine oxidative metabolites appeared to be mainly under genetic control. Intraindividual variations were much smaller than interindividual variations. Regardless of zygosity, intratwin correlation coefficients for antipyrine were similar for twins living apart and twins living together. This comparison 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.