Interethnic differences in debrisoquin and mephenytoin hydroxylation have been compared between normal white (n = 183) and Japanese (n = 100) subjects with the 8-hour urinary metabolic ratio of debrisoquin and the urinary S/R enantiomeric ratio of mephenytoin to identify extensive (EM) and poor (PM) metabolizers. In white subjects the frequency of PMs was 8.7% and 2.7% for debrisoquin and mephenytoin, respectively. In contrast, in Japanese subjects no PMs of debrisoquin were identified, while the incidence of PMs of mephenytoin was 18%. These substantial differences (P less than 0.001) in polymorphic distributions of oxidative drug metabolizing ability have implications for interethnic efficacy and toxicity of drugs and other xenobiotics that are metabolized by the involved cytochrome P-450 isozymes.

We measured plasma concentrations of 1,25-dihydroxyvitamin D (1,25-(OH)2D) in the course of a 6-to-37-month survey of four children with hypercalcemia and an elfin facies (Williams syndrome). Levels of 1,25-(OH)2D were elevated (160 to 470 pg per milliliter) during the hypercalcemic phase of the disease, when the children were five to nine months old, and they decreased thereafter. Plasma 1,25 (OH)2D levels were higher than those found in three children (16 to 60 months old) with the elfin facies syndrome and no hypercalcemia (42 to 71 pg per milliliter) and eight children (1 to 36 months old) with hypercalcemia and no dysmorphy (12 to 140 pg per milliliter), including two children with vitamin D intoxication. Hypercalcemia in the three children with elfin facies was controlled by a low-calcium diet. Serum calcium levels fell to the normal range, and plasma 1,25-(OH)2D levels were normal for age (18 to 105 pg per milliliter) at 14 to 47 months of age, even after appropriate therapy had been discontinued. These observations suggest that hypercalcemia may be the consequence of abnormal synthesis or degradation of 1,25-(OH)2D in children with the elfin facies syndrome.

Because of the large interethnic differences in the incidence of poor metabolizer phenotypes, French Caucasians have been studied for two independent polymorphisms, debrisoquine/dextromethorphan and mephenytoin metabolism. One hundred and thirty-two unrelated French Caucasians were phenotyped using oral doses of dextromethorphan 20 mg and mephenytoin 100 mg. Individual dextrorphan excretion over 8 h and the dextromethorphan/dextrorphan metabolic ratio were calculated. Extensive metabolizers were taken as subjects with a high dextrorphan output (15.56 mumol/8 h) and a low metabolic ratio (0.0023), and poor metabolizers were those with a low dextrorphan output (0.39 mumol/8 h) and a high metabolic ratio (7.00). Individual 4-hydroxymephenytoin excretion and mephenytoin hydroxylation indices were also determined. Extensive metabolizers eliminated large amounts of 4 hydroxymephenytoin (133.2 mumol/8 h) and had a hydroxylation index of 1.99, and poor metabolizers, because of impaired mephenytoin metabolism, had a high hydroxylation index (277). The incidence of the poor metabolizer phenotype was 3% for dextromethorphan (95% confidence limits 0.5%-8.5%) and 6% for mephenytoin (95% confidence limits 2%-12.5%).

It is well recognized that wide interindividual variation in the efficiency of elimination can be anticipated for drugs which are predominantly eliminated by metabolism. The capacity of an individual to metabolize such a drug is dependent upon genetic and environmental factors. Numerous studies have investigated the impact of environmental factors [for reviews see (1-3)] but less information is available concerning genetic regulation. An important role for genetic factors was initially suggested by twin and family studies. Interindividual differences in drug metabolism in sibling pairs are less in identical (monozygotic) twins than in fraternal (dizygotic) twins (3). The first reports of the extent to which genetic variations contribute to interindividual variations were related to N-acetylation reactions in 1954 (4). However, it was not until 1975 that genetic polymorphisms of oxidative metabolism were reported, with the simultaneous publication of two genetic defects associated with sparteine oxidation in a German population (5) and debrisoquine hydroxylation in an English population (6). These defects were subsequently shown to be two expressions of the same gene defect. A number of other drugs have also been shown to exhibit polymorphic distribution in the efficiency of their oxidation. In some instances, defects in oxidation have been linked with debrisoquine and sparteine metabolism, in other instances, the defects in oxidation have been independent. These differences probably reflect the fact that cytochrome P-450 exists as a family of isozymes with selective but overlapping substrate and product specificity. A number of previous reviews have discussed this topic (7-10). The objective of the present review is to develop the evidence for, and pharmacokinetic and clinical consequences of, polymorphic distribution of oxidative drug metabolism. Recent advances in our understanding of the molecular basis that determines drug metabolism and its genetic regulation are presented. Finally, we have evaluated methods used in the identification of drugs that cosegregate in their metabolism.