G. Thomas Passananti

Genetic and environmental factors affecting ethanol metabolism in man.

The relative contribution of genetic and environmental factors to maintaining twofold differences in rates of ethanol elimination from plasma was examined in 14 sets of nonmedicated, nonhospitalized healthy twins. After a single oral dose of 1 ml. per kilogram of 95 per cent ethanol, intrapair differences in rates of elimination were less in identical than in fraternal twins. Thew results indicate that individual differences in rates of ethanol elimination among the 28 twins were genetically controlled and that environmental factors played a negligible role. In 6 prisoners in solitary confinement, rates of ethanol metabolism increased in 3 but declined in the remaining 3 after 21 days of ethanol administration. Rates of antipyrine elimination from plasma were accelerated by ethanol administration in each of the 6 volunteers. Considerable individual variation occurred in the degree to which ethanol shortened plasma antipyrine half‐lifes; reduction ranged from 4 to 37 per cent of the initial antipyrine half‐life. These results suggest that ethanol administration for 21 days at this dosage fails to alter consistently the rate of its own metabolism but increases antipyrine metabolism in all subjects to varying extents.

Impairment of Drug Metabolism in Man by Allopurinol and Nortriptyline

Abstract Normal medical students received either allopurinol or nortriptyline. To quantitate changes in rates of drug metabolism produced by allopurinol or nortriptyline administration, the plasma half-lives of antipyrine or bishydroxycoumarin were determined both before and 24 hours after the last dose of allopurinol or nortriptyline. Allopurinol and nortriptyline each markedly prolonged the plasma half-lives of antipyrine and bishydroxycoumarin; large individual variations in prolongation times were observed. In rats, allopurinol and nortriptyline each reduced the activity of hepatic microsomal drug-metabolizing enzymes and slightly lowered the level of cytochrome P-450. These results in rats support the interpretation that in man prolongation of antipyrine and bishydroxycoumarin half-lives after allopurinol or nortriptyline pretreatment is produced by reduced rates of drug biotransformation in liver microsomes. Lowering of the usual dose and close monitoring of blood levels of drugs given simultaneousl...

Studies on the disposition of antipyrine, aminopyrine, and phenacetin using plasma, saliva, and urine.

In normal male subjects, the half‐lives of antipyrine, aminopyrine, or phenacetin were not significantly different from the half‐lives of each drug in saliva. Apparent volumes of distribution (aVd) in plasma and saliva differed by the extent to which each drug has been reported to bind to plasma proteins. Thus, the aVd of antipyrine in plasma and saliva was similar; there were significant differences in aVdfor aminopyrine; even greater differences were observed for penacetin. The expression 1 − aVd (p)/aVd (s) equals the fraction of the drug bound to plasma proteins. Rates of appearance in the urine of metabolites of antipyrine and aminopyrine were measured. General equations were used to show the relationship between half‐life for elimination of the parent drug from the body and rate of excretion of metabolites. There were significant correlations between the half‐life for elimination of antipyrine from the body and the half‐life for production of 4‐0H antipyrine (r = 0.90), as well as between the plasma half‐life of aminopyrine and the half‐life of 4‐aminoantipyrine (r = 0.95). No significant correlation was observed in the same individual between the plasma half‐lives of antipyrine and phenacetin (r = 0.05, p < 0.05), of aminopyrine and phenacetin (r = 0.11, p < 0.05), or of antipyrine and aminopyrine (r = 0.50, p < 0.05).

Altered plasma half‐lives of antipyrine, propylthiouracil, and methimazole in thyroid dysfunction

In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half‐lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half‐lives ± S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 ± 1.4 hr, 6.7 ± 1.0 hr, and 9.3 ± 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 ± 1.2 hr, 4.3 ± 0.7 hr, and 6.9 ± 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half‐lives of these drugs were prolonged to 26.4 ± 4.0 hr, 24.7 ± 34.5 hr, and 13.6 ± 4.8 hr, respectively. Return to the euthyroid state restored plasma half‐lives to or toward normal. Alterations in plasma drug half‐lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.

Hepatic Drug Metabolism in Rats: Impairment in a Dirty Environment

Reduction of aniline hydroxylase activity, ethylmorphine N-dementhylase activity, and cytochrome P-450 content occurred in hepatic microsomes of rats kept under dirty conditions, defined as accumulation for 1 week of urine and feces in pans under the wire mesh cages. In comparison with rats that had urine and feces removed twice daily from such pans, rats kept over Kimpak bedding or over Litter Green, changed twice daily, also showed reduced drug-metabolizing activity in hepatic microsomes, but to a lesser degree than the dirty rats. Placement of a filter top on cages for 1 week also decreased drug-metabolizing activity. These experiments suggest that the relative cleanliness of an animals environment can influence hepatic microsomal drug metabolism.

Impairment of drug metabolism by disulfiram in man

Disulfiram was administered for either 4 or 10 days to young, otherwise nonmedicated normal volunteers. In all subjects disulfiram prolonged the antipyrine half‐life and reduced urinary vanilmandelic acid (VMA) excretion; after disulfiram was discontinued, antipyrine half‐lives and VMA excretion returned toward normal. These results suggest the possibility of toxicity from dmg accumulation when certain other therapeutic agents are administered simultaneously with disulfiram. Such toxicity from diphenylhydantoin or warfarin has been reported in isolated case studies of patients receiving disulfiram. Since disulfiram administration alters catecholamine metabolism, patients receiving disulfiram should not be expected to exhibit normal parameters of catecholamine turnover. Effects of disulfiram on antipyrine and catecholamine metabolism reveal that disulfiram is not a selective inhibitor of aldehyde dehydrogenase but exerts several discrete inhibitory actions which should be recognized during its administration.

Antipyrine metabolism during the menstrual cycle

Two studies were initiated to determine the effect of the menstrual cycle on antipyrine metabolism. In the first study a relatively large oral dose of antipyrine (15 mg/kg) was given on days 3, 5, 10, 14, 16, 20, and 25 after the onset of menstruation. Salivary antipyrine half‐lifes (t½s) declined progressively, suggesting that the long‐term administration of this dose had stimulated antipyrine metabolism. To minimize this possible induction, in the second study a much smaller dose of antipyrine (1 mg/kg) was given on the same days of the cycle as in the first study. There was no induction. In both experiments, the menstrual cycle had little or no effect on the mean salivary t½, mean metabolic clearance rate, or apparent volume of distribution of antipyrine. In the second, men served as controls. The mean kinetic parameters for the men did not differ from those for the women. Although individuals of each sex varied from day to day in each kinetic parameter, the magnitude of the intraindividual variability in antipyrine metabolism was the same for both. The mean intraindividual coefficient of variation for antipyrine t½s was 14.4 ± 1.6% (SE) in women and 12.4 ± 1.3% (SE) in men. No consistent pattern for either sex was observed in the day‐to‐day variations in the means of the kinetic parameters investigated. Several women in whom the t½ rose or fell at midcycle were found to have a different pattern when reexamined 6 mo later.

Failure of Indomethacin and Warfarin to Interact in Normal Human Volunteers

In young, normal, male Caucasian volunteers, two different double-blind, placebo-controlled, randomized studies were performed to determine whether indomethacin interacts in a clinically significant fashion with warfarin. In the first study, stabilized hypoprothrombinemia was achieved by daily oral warfarin administration for at least 11 days; then indomethacin was administered concurrently with warfarin for five more days. During this five-day period failure of indomethacin to alter the degree of hypoprothhrombinemia induced by warfarin indicated that indomethacin does not interact with warfarin in vivo in a clinically significant fashion. A similar conclusion was drawn from results of the second experiment, in which plasma warfarin concentrations and prothrombin times were measured after a single oral dose of warfarin administered both before and after ten consecutive days of oral indomethacin administration. Thus, these studies suggest that warfarin may be given to patients receiving indomethacin and indomethacin may be administered to patients on warfarin without intensification or diminution of the normally expected hypoprothrombinemie effects of the dose of warfarin in that individual.

High levels of methylxanthines in chocolate do not alter theobromine disposition

Theobromine disposition was measured twice in 12 normal men, once after 14 days of abstention from all methylxanthines and once after 1 week of theobromine (6 mg/kg/day) in the form of dark chocolate. Mean theobromine t½, apparent volume of distribution, and clearance after abstinence from all methylxanthines were 10.0 hours, 0.76 L/kg, and 0.88 ml/min/kg. High daily doses of chocolate for 1 week did not change these values. After subjects abstained from methylxanthines, urinary radioactivity over 72 hours after a single, oral dose of [8‐14C]theobromine consisted of 42% 7‐methylxanthine, 20% 3‐methylxanthine, 18% theobromine, 10% 7‐methyluric acid, and 10% 6‐amino‐5[N methyl‐formylamino]‐1‐methyluracil. A week of daily theobromine consumption in the form of dark chocolate also did not alter this urinary profile of theobromine and its metabolites. Although these results might appear to differ from other reports of inhibition of theobromine elimination after five consecutive daily doses of theobromine in aqueous suspensions, both the rate and extent of absorption of theobromine in chocolate were less then that of theobromine in solution. Relative bioavailability of theobromine in chocolate was 80% that of theobromine in solution. This reinforces the fundamental principle that both the metabolic and the therapeutic consequences of a particular chemical can differ when that chemical is given in the pure compared with the dietary form.

Sources of interindividual variations in acetaminophen and antipyrine metabolism

Our goal was to compare and contrast in the same normal twins the relative contribution of genetic and environmental factors to large interindividual variations in the metabolism of acetaminophen (APAP) and antipyrine. These drugs were selected because they are biotransformed by different mechanisms. A single oral dose of APAP (10 mg/kg) was given to six sets of monozygotic (MZ) and six 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 formation of the sulfate and glucuronide conjugates, as well as in the overall rate constant for APAP elimination. Intratwin variations for each measurement were as target within MZ as within DZ twinships, suggesting that predominantly environmental rather than genetic factors maintained interindividual variations. Two other observations 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 different results were obtained when these twins received antipyrine. After a single oral dose of antipyrine (18 mg/kg), 500% interindividual variations in rate constants for formation of the three main oxidative metabolites of antipyrine appeared to be mainly under genetic control. Also for antipyrine and its principal metabolites, intraindividual variations were much smaller than interindividual variations. In contrast to the results with APAP, regardless of zygosity, intratwin correlation coefficients for antipyrine were similar for twins living apart and twins living together. This comparison between APAP and antipyrine metabolism in the same carefully selected normal twins under apparently uniform environmental conditions 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.