Enhanced drug metabolism in cigarette smokers.

The effect of cigarette smoking on salivary antipyrine disappearance rate, and as an index of hepatic drug metabolism, was studied in 42 healthy subjects. Antipyrine half life was significantly shorter in smokers compared with non-smokers. To determine whether this difference was due solely to tobacco consumption eight subjects were restudied two months after they stopped smoking. The mean antipyrine disappearance rate in this group increased by 23% in contrast to that of a control group, which did not alter. Cigarette smoking contributes to the considerable variation in interindividual rates of drug metabolism.     

Antipyrine,paracetamol, and lignocaine elimination in chronic liver disease.

The plasma half lives of antipyrine, paracetamol, and lignocaine given by mouth were measured in 23 patients with stable chronic liver diseases of varying severity. Fifteen patients received all three drugs and 19 at least two. The half life of paracetamol was abnormally prolonged in nine out of 17 patients (mean 2-9 hours, normal 2-0 hours), of antipyrine in 10 out of 19 patients (mean 30-4 hours, normal 12-0 hours), and of lignocaine in 19 out of 21 patients (mean 6-6 hours, normal 1-4 hours). Prolongation of the half lives of all three drugs was significantly correlated with an increase of the vitamin-K1-corrected prothrombin time ratio and a reduction in serum albumin concentration. There was no correlation with serum bilirubin concentration or serum alanine aminotransferase activity. This suggests that impaired drug elimination was related to depressed hepatic protein synthesis. Considerable prolongation of the half life of one drug was invariably associated with delayed elimination of the others. The half life of lignocaine, however, was always the most prolonged and was a highly sensitive indicator of hepatic dysfunction. The pharmacokinetic characteristics of a drug as well as the severity of liver disease should be taken into account when considering drug dosage in patients with chronic liver disease.     

Effect of Age and Sex on Human Drug Metabolism

The capacity of inpatients in a geriatric hospital to metabolize drugs was measured. The mean plasma half-life values with antipyrine and with phenylbutazone were found to be 45% and 29% greater respectively in patients than in young controls. When women alone were considered the half-life of antipyrine was 78% longer in the elderly group. In a number of elderly individuals the rate of metabolism of these two drugs was found to be extremely slow. This decreased ability to metabolize drugs may contribute to the known high incidence of adverse drug reactions in the elderly.Within the control group a significant sex difference in the rate of antipyrine metabolism was found, the mean half-life being 30% longer in the males. It is clear from these results that the age and sex of subjects must be taken into account in studies of human drug metabolism.     

Abnormal Drug Metabolism after Barbiturate and Paracetamol Overdose

Drug-metabolizing capacity has been assessed by serial measurements of the plasma antipyrine half life in 11 patients with severe barbiturate intoxication and in 17 patients with acute hepatic necrosis due to paracetamol overdosage. Drug metabolism was strikingly enhanced after barbiturate over-dosage, and this effect was still present six weeks later. In contrast the antipyrine half life was greatly prolonged in patients with paracetamol-induced acute hepatic necrosis but returned to normal or near-normal values within seven to 21 days.     

Impairment of human antipyrine metabolism by piroxicam

The pharmacokinetics of a single oral dose of antipyrine was determined in healthy young volunteers (18-28 years), both 3 days before piroxicam, ketoprofen, or naproxen administration and on the following day of their discontinuation. In all subjects treated with piroxicam (10, 20, and 40 mg daily) for 5 consecutive days, the rate of salivary antipyrine elimination slowed. Antipyrine half-life was prolonged and metabolic clearance was reduced significantly (p less than 0.01) proportional to the dose administered. After piroxicam was discontinued, both pharmacokinetic parameters of antipyrine returned toward normal. No significant modification in antipyrine half-life or metabolic clearance rate was demonstrated after pretreatment with ketoprofen (50, 100, and 200 mg daily) or naproxen (250 and 500 mg daily). The impairment on antipyrine disposition produced by piroxicam has been interpreted as a consequence of a reduction in the activity of hepatic microsomal drug-metabolizing enzymes, particularly the cytochrome P-450 system. These results suggest the possibility of drug accumulation and toxicity when certain other therapeutic agents are administered simultaneously with piroxicam. For the same reason, it is recommended to bear in mind the potential danger of long-term piroxicam therapy on the oxidative degradation of steroid hormones and other endogenous compounds that are metabolized by the mixed-function oxidase system.     

Why Patients Choose Homeopathy

Interviews with 100 homeopathic patients in the San Francisco Bay Area show that for the most part the patients are young, white and well-educated, and have white-collar jobs; most had previously tried mainstream medical care and found it unsatisfactory. Among the reasons for their dissatisfaction were instances of negative side effects from medication, lack of nutritional or preventive medical counseling, and lack of health education. Experiences with conventional physicians were almost evenly divided: nearly half of the subjects reported poor experiences, slightly fewer reported good experiences. Three quarters of the patients suffered from chronic illness and about half considered their progress to be good under homeopathic care. The majority were simultaneously involved in other nontraditional health care activities.     

Failure of Corynebacterium parvum to inhibit antipyrine metabolism in man

Summary In animals, Corynebacterium parvum lowers the rate of drug metabolism and enhances the pharmacologic effect of drugs requiring hepatic microsomal enzyme activity for elimination. A pilot study was conducted to assess this drug interaction in patients given clinical protocol doses of C. parvum. In individual patients, C. parvum did not reduce microsomal drug metabolism as measured by antipyrine half-life. Conversely, antipyrine elimination appeared to be enhanced in 10 of 14 patients. Results from this small heterogenous patient group are not definitive, and further studies are needed to determine the clinical significance of the effects of nonspecific immunotherapy on drug metabolism.     

Impaired Lignocaine metabolism in patients with myocardial infarction and cardiac failure.

Plasma concentrations of lignocaine were measured during and after infusion of lignocaine at 1.4 mg/min for 36-46 hours in 12 patients with myocardial infarction and one patient with cardiac failure due to uncontrolled ventricular tachycardia. In six patients without cardiac failure the plasma concentrations of lignocaine rose progressively during the infusion and the mean lignocaine half life was 4.3 hours compared with 1.4 hours in healthy subjects. Mean plasma lignocaine concentrations were significantly higher in seven patients with cardiac failure, and concentrations also rose during the infusion and the half life was considerably prolonged to 10.2 hours. Lignocaine concentrations rose rapidly to toxic levels when cardiogenic shock developed in one patient and did not fall when the infusion was stopped. The mean plasma antipyrine half life was moderately prolonged (19.4 hours) in a larger group of patients with myocardial infarction and cardiac failure but returned to normal during convalescence (13.2 hours). The metabolism of lignocaine is grossly abnormal in patients with cardiac failure and cardiogenic shock after myocardial infarction.     

Cimetidine and ranitidine: comparison of effects on hepatic drug metabolism.

Paired studies of hepatic microsomal function were conducted in eight subjects during treatment with two histamine H2 antagonists, cimetidine and ranitidine. Cimetidine but not ranitidine inhibited the metabolism of antipyrine (phenazone) and demethylation of aminopyrine (aminophenazone) as measured by breath 14CO2 production after intravenous injection of 14C-aminopyrine. These results suggest that the metabolic inhibitory actions on the liver may be separated from H2 antagonist effects, and that ranitidine has an advantage over cimetidine by not inhibiting microsomal drug oxidative function.     

Changes in Human Drug Metabolism after Long-term Exposure to Hypnotics

The influence of the newer, non-barbiturate hypnotics Mandrax (diphenhydramine-methaqualone) and nitrazepam on drug-metabolizing capacity was assessed and compared with the effect of amylobarbitone, a known inducer of drug-metabolizing enzymes. Plasma antipyrine and phenylbutazone half-lives and urinary output of 6β-hydroxycortisol were used as indices. Volunteer subjects were exposed to therapeutic amounts of these agents and, in the case of Mandrax and barbiturates, further studies were carried out in dependent patients.Mandrax but not nitrazepam increased the rate of drug metabolism, presumably by enzyme induction. The degree of induction was comparable with that produced by hypnotic doses of amylobarbitone. The Mandrax-dependent and barbiturate-dependent patients were the fastest metabolizers studied. It is concluded that drug interactions resulting from interference with drug metabolism are as likely to occur with Mandrax as with barbiturates. On the other hand, it is unlikely that such drug interactions would occur with nitrazepam.     

Plasma levels of glibenclamide in diabetic patients during its routine clinical administration determined by a specific radioimmunoassay

Plasma concentration of glibenclamide in routine clinical practice was determined by a specific radioimmunoassay. In diabetic patients treated with glibenclamide for a month or longer, the drug level in fasting morning plasma was variable but the mean level paralleled the daily dose. After oral administration of 2.5 mg in healthy and diabetic subjects, the drug level reached peaks in 1.5 hours and declined to the half of the peak level in next 2-3 hours. The plasma glibenclamide profile after oral dose did not differ significantly in patients with secondary failure to the drug. Comparison of a single-dose and divided-dose schedules of 5 mg glibenclamide revealed that plasma drug level increased each time after administration. Plasma glucose and insulin concentrations did not differ significantly at most times of the day but there was a tendency that increment of plasma glucose after meal was suppressed by a dose taken immediately before a meal. The relationship of blood level of glibenclamide to clinical effectiveness may be rather indirect and needs to be elucidated.     

The effects of malotilate on hepatic drug metabolizing systems in different strains of rats

1. In Sprague-Dawley (SD) rats treated for 7 days with malotilate (MAL:250 mg/kg, p.o.), cytochrome P-450 and b5 contents, aminopyrine N-demethylase and heme oxygenase activities were significantly increased. In Wistar rats, cytochrome b5 content and heme oxygenase and delta-aminolevulinic acid synthetase activities were found to be significantly increased. 2. Among the antipyrine metabolites excreted in urine during the 24 hr after antipyrine (100 mg/kg, i.p.) administration, norantipyrine increased significantly in Sprague-Dawley rats, while a significant increase of 4-hydroxyantipyrine was observed in Wistar rats. 3. The serum dimethadione/trimethadione ratio was only found to be significantly increased in Sprague-Dawley rats. 4. These results indicate that malotilate may have inducible effects on hepatic drug metabolizing enzymes, and that it affects the various cytochrome P-450 isozymes from different strains of rat in different ways.     

Intravenous epoprostenol sodium does not increase hepatic microsomal enzyme activity in rats

Previous studies have indicated that epoprostenol may increase hepatic microsomal enzyme activity both in animals and humans. However, interpretation of the results of these studies may be confounded by the route of epoprostenol administration or small sample sizes. The primary objective of the present investigation was to evaluate the effects of epoprostenol (given as a continuous intravenous infusion) on hepatic microsomal enzyme activity in rats. Male Sprague Dawley rats (220–290 g) received infusions of either vehicle (glycine buffer, 1 mL/hr) or 0.2 μg/kg/min epoprostenol through a jugular vein cannula for 24 hr or 7 days. At the end of the infusion, a 25 mg/kg ix. bolus of antipyrine was administered and blood samples were collected over 6 hr. Serum antipyrine concentrations were determined by HPLC. Twenty-four hr post-infusion, hepatic microsomes were prepared, and cytochrome P-450 content was determined by difference spectroscopy. Cytochrome P-450 content and antipyrine clearance values determined from serum antipyrine concentration-time profiles were not significantly different between treatment groups. Antipyrine clearance [mean (SD)] in the 24-hr vehicle-treated group was 3.68 (0.49) mL/min/kg versus 4.35 (1.1)mL/min/kg in the epoprostenol-treated group. In the 7-day vehicle-treated rats, antipyrine clearance was 5.43 (1.0) mL/min/kg compared to 4.68 (0.61)mL/min/kg in epoprostenol-treated rats. A statistically significant effect of infusion duration was observed in the control group, i.e., antipyrine clearance in rats treated with vehicle for 7 days was significantly greater than that observed in rats treated with vehicle for 24 hr. However, the increase was less than 50%. These data suggest that when epoprostenol is administered as an intravenous infusion to rats, no significant alterations in hepatic microsomal enzyme activity occur. Based on these data, long term changes in heparic metabolism in response to chronic epoprostenol administration are nor expected.     

Pharmacoanthropology: drug metabolism

This is a report of similarities and differences among various ethnically defined populations with respect to their capacities to metabolize the prototype drugs antipyrine, caffeine, and debrisoquine. There were equal levels of the three main metabolites of antipyrine in the urine of Caucasians and Orientals; differences in antipyrine clearance between English and Indian subjects appeared to have environmental causes. Exploration of various metabolite ratios of caffeine in the urine of Caucasians and Orientals living in Canada showed three patterns: 1) no interethnic difference occurred in the ratio thought to indicate xanthine oxidase activity; 2) products of 7-demethylation and of hydroxylation of paraxanthine , both probably produced by cytochrome P-450, showed different averages in the populations; 3) the new secondary metabolite acetylformyl -methyluracil proved to be a useful indicator of the genetically controlled acetylator status, thereby confirming the well-known population difference for acetylator gene frequency. Analysis of data on debriosquine hydroxylation suggested that interpretation of the standardized metabolic ratio may be appropriate for Caucasian and Oriental groups but is misleading for published data from Saudi Arabia, Nigeria, and Ghana; even these two closely related West African populations seem to differ in debrisoquine metabolism.     

Effects of protein malnutrition and ascorbic acid levels on drug metabolism

The duration of action of drugs (or other environmental chemicals) is dependent on their rate of metabolic deactivation and elimination from the body. Termination of activity is achieved either through excretion of the drug via the kidney and bile or, more commonly, through metabolic deactivation by enzymes of the liver and other tissues. In recent years, it has become increasingly obvious that nutritional status is one of the major factors capable of modifying the pharmacological effect of drugs. Numerous studies have indicated that the process of drug metabolism may be affected by acute starvation, undernutrition, protein nutrition, and deficiencies of minerals, vitamins, and lipids. Although most of the evidence concerning the effects of nutrition on the metabolism of drugs has been derived from studies on experimental animals, there is significant fragmentary human data to show that the same effects may occur in man. This paper will discuss the influence of nutritional status with particular references to protein and ascorbic acid on the metabolism of foreign compounds including drugs. The interrelationships of nutrition and the metabolism of drugs are an important consideration in view of the widespread recurrence of primary malnutrition in the developing countries, and of secondary malnutrition in more affluent societies, especially in debilitated chronically ill patients, in postoperative patients, and in those whose dietary manipulations are carried out in weight-reducing regimens. The effects of nutrition on drug metabolism may be viewed as an extension of the search for one of the environmental factors that modify drug action.     

Dipyrone and aminopyrine are effective scavengers of reactive nitrogen species

Reactive nitrogen species (RNS), namely nitric oxide (NO*) and peroxynitrite (ONOO-) are produced in the inflammatory sites and may contribute to the deleterious effects of inflammation. The aim of the present study was to evaluate the putative scavenging effect of a particular group of non-steroidal anti-inflammatory drugs (NSAIDs), the pyrazolone derivatives dipyrone, aminopyrine, isopropylantipyrine, and antipyrine against RNS, using in vitro non-cellular screening systems. The results obtained showed that dipyrone and aminopyrine were highly potent scavengers of NO* and ONOO- while antipyrine exerted little effect and isopropylantipyrine no effect whatsoever against these two RNS and that, in the presence of bicarbonate, the scavenging potencies of both dipyrone and aminopyrine were slightly decreased. It could thus be inferred that the observed scavenging effects may be of therapeutic benefit for patients under anti-inflammatory treatment with dipyrone and aminopyrine in the case of overproduction of RNS. On the other hand, the possible depletion of physiological NO* concentrations, namely at the gastrointestinal tract as well as the formation of reactive derivatives of aminopyrine and/or dipyrone, resulting from their reaction with RNS, may otherwise be harmful for these patients.     

Evaluation of the capacity of the liver for phenazone biotransformation in patients with uremia on peritoneal dialysis

This work aimed at establishing whether liver ability to biotransformation of drugs expressed by antipyrine kinetics is disturbed in peritoneally dialysed patients with end-stage renal failure. The investigations were carried out in 10 uraemic patients using the antipyrine test and comparing antipyrine kinetics with those obtained in 13 healthy individuals. At the time of investigations, standard clinical tests of liver function were normal and HBs antigen was absent in all patients. It was shown that peritoneally dialysed patients with end-stage renal failure had not significantly changed antipyrine elimination as compared with the group of healthy controls: t0.5 = 13.2 +/- 6.8 v. 11.8 +/- 8.1 h, plasma clearance = 50 +/- 30 v. 34 +/- 21 ml/min (x +/- SD). The obtained results indicate that antipyrine kinetics is within normal range in uraemic patients regularly dialysed suggesting cytochrome P-450 in microsomes not being markedly reduced.     

Drugs and nutrition in old age

Drug effects are influenced by physiologic and pathologic changes that occur as a consequence of aging. The elderly may be more disposed to drug-induced nutrient depletion because of chronic illness, inadequate diet and long-term drug use. Digoxin, isoniazid, corticosteroids, diuretics and psychoactive agents pose special hazards to the nutritional status of elderly patients. On the other hand, dietary factors, such as protein levels or vitamin deficiencies, may be important determinants of age-related changes in drug disposition or toxicity.     

Changes in hepatic biotransformation in patients treated with beta-adrenergic drugs and prazosin

Biotransformation in the liver was tested with antipyrine elimination test in 41 patients treated with prazosin for 3 months (Minipress Pfizer, 1-4 mg a day) or prazosin combined with beta-adrenolytic agents (propranolol 40-80 mg; metoprolol 100-200 mg daily). It was found that T0.5 of antipyrine is shortened in patients treated with prazosin alone by 3 h/p greater than .05/while in the patients treated with prazosin whom previously--adrenalytics were given by 7.5 h/p greater than 0.01/. Antipyrine half-life during the treatment with beta-adrenolytics was prolonged by + 5.3 h/p greater than .05/while during the combined therapy with these agents and prazosin - 3.8 h. These results indicate that prazosin contrary to beta-adrenolytics, does not affect biotransformation in the liver. During combined therapy with prazosin and beta-adrenolytics, unfavourable effect of the latter in prevailing. Replacement of beta-adrenolytics with prazosin may prevent unfavourable effect of the former on liver functioning and may increase the safety of the hypotensive treatment.