Stimulation Of Drug Metabolism Research Articles

Effects of ethanol and sorbitol on mixed-function oxidation in perfused rat livers

Ethanol (20 mM) caused 50–90% inhibition of rates of mixed-function oxidation of p-nitroanisole, 7-ethoxycoumarin and benzo(a)pyprene in perfused rat livers; however, the microsomal metabolism of these substrates was unaltered by low concentrations of ethanol. The metabolism of ethanol was required for this inhibition in the perfused liver. In contrast to ethanol, sorbitol stimulated rates of p-nitroanisole O-demethylation in perfused livers from fasted, phenobarbital-treated rats. Both sorbitol and ethanol infusion decreased the hepatic NAD +/NADH ratio; however, the NADP +/NADPH ratio was decreased by sorbitol but increased by ethanol. Stimulation of drug metabolism by sorbitol was abolished by pretreatment of fasted rats with 6-aminonicotinamide, an inhibitor of the pentose phosphate shunt. The data indicated that sorbitol stimulated p-nitroanisole metabolism by providing NADPH via the pentose phosphate shunt. The changes in intracellular concentrations of NADPH produced by ethanol and sorbitol correlated directly with changes in hepatic content of citrate and aspartate. These data suggest that inhibition of the citric acid cycle by ethanol decreases the movement of mitochondrial reducing equivalents into the cytosol via substrate shuttle mechanisms.

Regulation of NADPH-dependent mixed-function oxidation in perfused livers: Comparative studies with sorbitol and ethanol

Sorbitol and ethanol were shown to have opposite effects on p-nitroanisole O-demethylation in perfused livers from fasted, phenobarbital-treated rats. Sorbitol (2 mM) stimulated drug metabolism by 50% while ethanol (20 mM) caused 80% inhibition. Both sorbitol and ethanol infusion decreased the NAD +/NADH ratio and increased fluorescence of pyridine nucleotides monitored from the liver surface; however, the NADP +/NADPH ratio was decreased by sorbitol but tended to be increased by ethanol. Stimulation of drug metabolism by sorbitol was abolished by pretreatment of fasted rats with 6-aminonicotinamide, an inhibitor of the pentose phosphate shunt, but was not affected by aminooxyacetate, a transaminase inhibitor. These results indicate that sorbitol stimulated p-nitroanisole metabolism by providing NADPH via the pentose phosphate shunt. Ethanol and sorbitol caused changes in intracellular concentrations of NADPH in livers from fasted rats which correlated directly with changes in hepatic levels of citrate and aspartate. Furthermore, aspartate infusion reduced the inhibition of p-nitroanisole O-demethylation by ethanol. This inhibition was also reversed partially by sorbitol in livers from 6-aminonicotinamide-treated rats. It is concluded that ethanol inhibits mixed-function oxidation primarily by decreasing the concentrations of citric acid cycle intermediates which leads to depletion of cytosolic NADPH.

Role of drug metabolism in protection against chlorphentermine-induced pulmonary phospholipidosis in adult rat

Daily oral administration of either 20 or 60 mg/kg chlorphentermine for 1 week to adult rats produced a dose-related decrease in body and liver weight. In lung, the chlorphentermine-induced accumulation of alveolar foam cells and increase in relative tissue to body weight was also dose dependent. Although both doses of this anorectic drug failed to markedly alter the activity of hepatic and pulmonary microsomal aniline hydroxylase, a significant elevation in aminopyrine N-demethylase was noted in both tissues of rats given 60 mg/kg chlorphentermine. Treatment with phenobarbital (30 mg/kg/day) for 1 week stimulated the activities of pulmonary and hepatic aniline hydroxylase and aminopyrine N-demethylase. Simultaneous administration of phenobarbital and either dose of anorectic prevented the chlorphentermine-induced decrease in body and liver weight as well as increase in relative lung weight. In addition, phenobarbital blocked the development of alveolar foam cells in rats administered 20 mg/kg chlorphentermine and reduced this number in animals receiving the higher dose. Concurrent administration of phenobarbital and chlorphentermine elevated the activities of hepatic aniline hydroxylase and aminopyrine N-demethylase to the same extent as barbiturate alone. Although simultaneous 20 mg/kg anorectic and phenobarbital increased both pulmonary enzymes in a manner similar to barbiturate alone, a synergistic rise was noted in aminopyrine N-demethylase activity of lungs from rats given the higher chlorphentermine dose and phenobarbital. Our results suggest that one of the mechanisms which contributes to the protection afforded by phenobarbital in diminishing chlorphentermine-induced pulmonary phospholipidosis appears to be through stimulation of drug metabolism.

Stimulation of drug metabolism by folate replacement in folate-deficient epileptic patients [proceedings

Stimulation of drug metabolism by folate replacement in folate-deficient epileptic patients [proceedings

Differential stimulation of diphenhydramine, pethidine, morphine and aniline metabolism by chronic methaqualone treatment.

In the present study, the effect of chronic oral methaqualone treatment (60 mg/kg/24 h for 25 days) was examined on the metabolism of diphenhydramine, pethidine, morphine and aniline in rat liver microsomes. Such chronic methaqualone treatment caused an enhancement of microsomal drug metabolizing enzymes catalyzed N-demethylations of diphenhydramine, pethidine, morphine and aromatic hydroxylation of aniline. A single oral dose of methaqualone (60 mg/kg) did not result in any significant change in the activities of drug metabolizing enzymes. Methaqualone inhibited drug metabolizing enzymes when used at final concentrations of 1 and 3 mmol/l in vitro. These observations led to suggest that the stimulation of drug metabolism noted in this study is possibly due to the induction of microsomal drug metabolizing enzymes. It was interesting to note that the induction of N-demethylases by repeated methaqualone intake was differential in nature since diphenhydramine and morphine N-demethylases were induced about twofold whereas pethidine N-demethylase was enhanced about fourfold. These results should be of extreme importance in understanding the biochemical mechanism of the specific and differential drug tolerance by continued methaqualone abuse and its possible interaction with other drugs.

Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance.

Eleven patients with hepatic cirrhosis or cholestasis were treated with rifampicin for 7 to 132 days. Ten patients received hexobarbital (7.32 mg/kg) and five received tolbutamide (20 mg/kg) by i.v. infusion prior to and after rifampicin treatment; plasma concentrations of the two test compounds were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 624 to 262 min and that of tolbutamide from 292 to 160 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased more than two-fold and that of tolbutamide almost two-fold. The results suggests that rifampicin is able to stimulate hepatic drug metabolism in patients with liver disease. It was apparent in general that the induction did not lead to improvement of hepatocellular function during disease as judged by laboratory findings.

Stimulation of drug metabolism by ascorbic acid in weanling guinea-pigs

Drug metabolism activities such as O-demethylase and N-demethylase and liver microsomal electron transport components including cytochrome P-450 and NADPH-cytochrome P-450 reductase were determined in weanling guinea-pigs under vitamin C deficiency as well as with normal and high intake of the vitamin. Animals depleted of the vitamin for only 8 days, with no signs of scurvy or weight loss, had decreased drug enzyme activities. Further depletion of the vitamin resulted in marked reduction of the microsomal drug-metabolizing system. Furthermore, administration of high amounts of ascorbic acid (2–200 mg/day) led to significant increases in liver drug oxidation activities and electron transport components. Studies of K m values in microsomes from vitamin C-deficient, normal and animals given high supplements of vitamin C showed no difference in the apparent affinity or V max of a typical drug oxidation reaction, N-demethylation. Specificity studies indicate that ascorbyl palmitate or d-isoascorbic acid can replace the vitamin, in part, in maintaining drug metabolism.

Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme induction and increased hepatic blood flow.

The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179+/-15 to 239+/-27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.

Stimulation of drug metabolism in man by tricyclic antidepressants.

Plasma antipyrine half-lives were measured in thirty adult subjects before and after 7 and 28 days treatment with one of five tricyclic antidepressants. Overall, considering the five antidepressants together, there was a small but significant reduction in half-life after both periods of treatment. In four subjects studied, increased urinary output of 6β-hydroxycortisol following chronic nortriptyline treatment provides further evidence of a stimulatory effect of tricyclic antidepressant on drug metabolism. In a separate study, the induction effect of tricyclic antidepressants was found to be much less marked than that with amylobarbitone. It would seem therefore that tricyclic antidepressants are less likely than barbiturates, to bring about drug interactions by altering drug metabolism.

Induction of liver microsomal drug metabolism and inhibition of microsomal ribonuclease activity by phenobarbital

Microsomal ribonuclease (RNase) activity was determined after the administration of phenobarbital (100 mg/kg, ip) to rats. Eighty percent inhibition of RNase activity occurred 48 hr prior to maximal stimulation of p-chloro- N-methylaniline demethylation. Thereafter, RNase activity increased to control levels. Inhibition of RNase activity was also observed in a dose-dependent manner when phenobarbital (25 mg/kg or 50 mg/kg twice daily) was administered to intact, adrenalectomized or hypophysectomized rats. These results suggested that RNase inhibition occurred during stimulation of drug metabolism in the absence of the pituitary or adrenal glands. Recombination experiments involving addition of 105,000 g liver supernatant fractions to control microsomes resulted in inhibition of RNase activity of the latter fractions. The administration of 3-methylcholanthrene (40 mg/kg, ip for 2 days) did not produce significant ( p > 0.05) inhibition of microsomal RNase. The results of this study suggested that RNase inhibition did not require an intact pituitary-adrenal axis during induction of drug metabolism by phenobarbital. The inhibition of RNase was probably due to the presence of a cytoplasmic inhibitor.

Nonspecific stimulation of drug metabolism in rats by methoxyflurane.

Nonspecific stimulation of drug metabolism in rats by methoxyflurane.

The influence of age, sex and drug treatment on microsomal drug metabolism in four rat strains

The present study describes the influence of sex, age and drug pretreatment on drug metabolism in four common strains of rats. Basal levels of activity of hepatic microsomal drug-metabolizing enzymes in the four strains varied considerably less than those reported in different rabbit and mouse strains. There was, in general, only a 2-fold variation in metabolic rate for a single drug. Young male and female Holtzman rats showed the lowest microsomal metabolism in all drug pathways examined. Phenobarbital pretreatment caused a stimulation of drug metabolism in young and adult, male and female rats of all strains. 3-Methylcholanthrene, on the other hand, often caused no change or decreased the rate. Evidence is presented which suggests that liver microsomes may contain a number of NADPH-dependent enzymes which differ in their rates of postpubertal development.