Theophylline Metabolism during the First Month of Life and Development

Bonati, Maurizio; Latini, R.; Marra, Giuseppina; Assael, B.M.; Parini, Rossella

doi:10.1203/00006450-198104000-00003

Cited by 38 publications

(20 citation statements)

References 11 publications

(19 reference statements)

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“…A diet high in charcoal-broiled beef induces to similar extents the metabolism of AP and theophylline (37), and high dietary protein can by itself induce both antipyrine and theophylline (39). Finally, cigarette smoking induces to similar extents the metabolism of AP and theophylline (14,19,20,41,42,(46)(47)(48).…”

Section: Discussionmentioning

confidence: 94%

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Polymorphism of theophylline metabolism in man.

Miller¹,

Slusher²,

Vesell³

1985

J. Clin. Invest.

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To determine whether genetic mechanisms control large interindividual variations in theophylline elimination in normal uninduced human subjects, and, if so, to test the possibility that these genetic factors are transmitted as a simple Mendelian trait, theophylline was administered to 79 unrelated adults, six sets of monozygotic twins, six sets of dizygotic twins, and six two-generation families. Thereafter, in urine collected from each subject at regular intervals for 48 h, concentrations of theophylline and its three principal metabolites were measured and rate constants of formation of these metabolites calculated.The twin study, designed to determine the relative contributions of genetic and environmental factors to large interindividual variation in theophylline elimination, revealed predominantly genetic control. Values for this genetic component, designated heritability (HI2), of interindividual variation in rate constants of metabolite formation were 0.61, 0.84, and 0.95 for 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid, respectively. HI2 for the overall theophylline elimination rate constant (kei) was lower (0.34).In the 79 unrelated adults, each distribution curve for rate constants of formation of each theophylline metabolite appeared to be trimodal. By contrast, the distribution curve for the overall theophylline elimination rate constant appeared to be either unimodal or bimodal. The extent of interindividual variation was fourfold for theophylline kei and 6-8-fold for the three principal metabolites. High correlations among the three rate constants in individual subjects suggested their regulation by a single shared factor.In six families carefully selected to be under near basal environmental conditions so that hepatic theophylline metabolism of each family member would be neither markedly induced nor inhibited, phenotypes for theophylline metabolite rate constants were assigned. This assignment of phenotype was made by the position of each family member's rate constant on the three distribution curves that were generated from the 79 unrelated subjects. In each family, pedigree analysis of the three phenotypes for each rate constant was consistent with their control by two alleles at a single genetic locus and with autosomal codominant transmission. Frequencies of the two alleles at each genetic locus controlling rate constants of formation of theophylline metabolites were similar (p = 0.49, 0.53, and 0.52). In the three families studied with antipyrine (AP) as well as with theophylline, AP

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Section: Discussionmentioning

confidence: 94%

“…It seemed reasonable that other drugs, such as AP, that also exhibit genetic polymorphism (12) (14,15,41,42). Such factors exerting unequal effects on the different isozymes of cytochrome P-450 could account not only for the correlations in Table V not being higher but also for the equivocal distribution curve of theophylline ke1.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of theophylline metabolism in man.

Miller¹,

Slusher²,

Vesell³

1985

J. Clin. Invest.

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“…Glycine conjugations are present in neonates at levels comparable to those of adults (31). Enzymatic systems responsible for theophylline oxidation and methylation to caffeine are active in premature neonates; whereas, the development of enzymes for oxidative demethylation do not develop for several months of life (34,35). The variation of theophylline metabolism observed during the first year of life is presented in Figure 2.…”

Section: Metabolismmentioning

confidence: 99%

Pharmacokinetics in the infant.

Milsap

Jusko

1994

Environ Health Perspect

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Processes controlling the absorption, distribution, metabolism, excretion, and pharmacologic effects of drugs are likely to be immature or altered in neonates and infants. Absorption may be affected by differences in gastric pH and stomach emptying rate. Low serum protein concentrations and higher body water composition can change drug distribution. Drug metabolism enzyme activity is typically reduced in the neonate, but rapidly develops over the first year of life. Renal excretion mechanisms are low at birth, but mature over a few months. Limited data are available on the pharmacodynamics of drugs; infants show greater sensitivity to d-tubocurarine. Developmental changes are rapid during the first weeks and months of life, thus requiring continual modification of drug dosage regimens designed for treating pediatric patients.

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“…Table I summarizes published data on theophylline urinary metabolites obtained from neonates and children [9][10][11][12][13][14]. Representative adult data for comparison are also provided.…”

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confidence: 99%