Theophylline metabolism: Variation and genetics

Abstract

Variation of theophylline [a bronchodilator used in the treatment of asthma] metabolism in 54 healthy, nonmedicated adults (13 monozygotic [MZ] twin pairs, 11 dizygotic [DZ] twin pairs and 6 single individuals) was assessed by kinetic study. Elimination rate constant, clearance (Cl), t1/2 [half-life] and apparent volume of distribution, as well as urine excretion of unchanged theophylline and of the 3 major metabolites (1-methyluric acid, 3-methylxanthine and 1,3-dimethyluric acid) were studied. Smokers and men had increased theophylline elimination rates compared to nonsmokers and women. Identical (MZ) twins resembled each other more closely than nonidentical (DZ) twins in the various kinetic parameters, but mean intrapair differences between MZ and DZ twins for all but 1 of the serum and urinary parameters examined (incuding t1/2) were not statistically significant. Estimates of heritability and of intrapair correlation coefficients showed a smaller contribution of genetic factors to variation in theophylline metabolism than had been reported for other drugs investigated by twin studies. In the family of the individual with the longest theophylline t1/2, the operation of a rare major gene retarding theophylline metabolism could not be excluded. A father and 2 of 4 children had very slow Cl. This finding would be consistent with, but does not prove, monogenic inheritance.