The use of two caffeine metabolite ratios for acetylator phenotyping was validated by demonstrating concordance with two sulfamethazine tests in 178 unrelated healthy subjects. The caffeine metabolites used for this purpose were 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), and 1-methylurate (1U). The ratio AAMU/(AAMU + 1X + 1U), referred to as molar ratio or N-acetyltransferase, was compared with the ratio AAMU/1X. The results indicated that, for screening purposes, the acetylator phenotype can be determined by analysis of a 6-hour urine sample after a cup of coffee or strong tea or a can of caffeine-containing soft drink. The ratio AAMU/1X is the ratio of choice for the study of subjects in whom variability of xanthine oxidase can be neglected; use of the ratio AAMU/(AAMU + 1X + 1U) appears appropriate for special purposes. Gender, ethnic origin, habitual or moderate consumption of coffee, tea, soft drinks, or ethanol, or cigarette smoking have little if any effect on the caffeine tests for acetylator phenotyping.

The genetically controlled mephenytoin p(4′)‐hydroxylation capacity was determined in 118 Caucasians and 70 Orientals. After an oral dose of 50 or 100 mg of racemic mephenytoin, the amount of p(4′)‐ hydroxymephenytoin in 24 h urine was measured by gas chromatography. Bimodal distribution was found with 9/70 (13%) Orientals and 5/118 (4%) Caucasians demonstrating deficient p(4′)‐hydroxylation. The statistically significant difference between Orientals and Caucasians (P less than 0.05) was accounted for by the high incidence of poor metabolizers among the Japanese subjects, 7/31 (23%). The frequency among Chinese subjects, 2/39 (5%), was similar to the frequency among Caucasians.

The extent of intersubject variation in diazepam free fraction was measured in fasting plasma of 74 unrelated subjects. Free fraction differences between subjects were significant and ranged from 0.97% to 1.99%. Diazepam free fraction in 29 males was normally distributed about a mean of 1.25% (range, 1.05% to 1.47%), but the distribution in females was skewed to higher free fractions and 40% had values above the highest in males. Albumin concentration (r = -0.27, p less than 0.002) and age (r = 0.44, p less than 0.001) only accounted for a small part of the variation. Within-pair variances were not greater in 11 dizygotic than in 18 monozygotic twin pairs, indicating a greater contribution of environmental than of genetic factors to diazepam binding. The prehemodialysis free fractions of diazepam in 9 uremic patients ranged from 3.44% to 6.69%, and decreased (p less than 0.005) in 7 after 6 hr of hemodialysis. In 10 subjects determination of intrasubject variation in diazepam free fraction between 14-hr fasting and 2-hr postprandial plasma samples indicated that because subjects differ in their pattern of change in free fraction (p less than 0.001), the overall decrease in mean free fraction did not achieve statistical significance (p = 0.10). The mean relative percent change in free fraction within subjects after feeding was 15.2%.

The apparent elimination half-lifes were determined for 4 drugs that undergo hydroxylation in men. Glutethimide (500 mg), amobarbital sodium (130 mg), antipyrine (1.0 gm), and sulfinpyrazone (400 mg) were each taken orally by 10 healthy men at weekly intervals. When the half-lifes in these 10 individuals were compared, positive correlations were found among 3 out of 4 drugs: glutethimide-amobarbital (r 0.69, p < 0.05), glutethimide-sulfinpyrazone (r 0.64, p < 0.05), and amobarbital-sulfinpyrazone (r 0.87, p < 0.01). If these data are generally valid, it would mean, for example, that one could, from the sulfinpyrazone half-life in a given sub;ect, predict the amobarbital half-life of the same individual within about ± 7 hours (30% of average half-life, while the interindividual differences could be 300%). Antipyrine half-life was not correlated with the half-life of any of the other 3 drugs. The urinary levels of 6f3-hydroxycortisol were also determined in the same sub;ects and compared with the half-lifes of the 4 drugs. The correlation coefficients taken singly were not statistically significant, but they were all negative and collectively seem to indicate an expected trend.