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.     

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.     

Genetic Control of Phenylbutazone Metabolism in Man

The purposes of the present investigation were to assess the genetic contribution to thevariability between individuals in the rate at which they metabolize phenylbutazone and to characterize the type of inheritance that controls the metabolism of the drug. The 155 persons investigated included 43 unrelated random individual subjects and the members of 28 two-generation family units. None of these subjects had taken drugs in the six months preceding the experiments. Each subject ingested an oral dose of phenylbutazone and the plasma half-life of the drug was determined. These non-pretreated plasma phenylbutazone half-lives suggest the existence of polygenic control, but the value of the data is marred by the frequency distribution being very skewed.The 142 persons given a second test, included 41 unrelated random subjects and 24 two-generation family units. A three-day course of oral phenobarbitone was followed by an oral dose of phenylbutazone and the plasma half-life of the latter determined. The phenobarbitone was given with the aim of “inducing” drugmetabolizing enzymes in the liver, thus rendering the environment more uniform. When the post-phenobarbitone half-lives were adjusted to a standard height they were approximately normally distributed. There was a significant regression of mean offspring value on mid-parent value, indicating that about 65% of the observed phenotypic variance of post-phenobarbitone plasma phenylbutazone half-lives is due to the additive effects of genes.Phenylbutazone metabolism in man is thus shown to be under polygenic control, and genetically controlled in a similar manner and to a similar degree to body height.Improved understanding of phenylbutazone metabolism may lead to improved therapeutic efficacy and a lower incidence of adverse reactions.     

Microsomal enzymes in malnutrition as determined by plasma half life of antipyrine.

Nutritional-pharmacological interactions were studied in a group of malnourished subjects. Antipyrine was used to evaluate mixed-function oxidase in man. The results indicated that the rate of disappearance of antipyrine from plasma was strongly influenced by the nutritional status of the individual. The half life of antipyrine was modified in undernourished subjects and those with nutritional oedema. This finding indicates that drug regimens may have to be adjusted in patients who have antipyrine half lives that are shorter or longer than normal. Otherwise drug treatment may be inadequate or, in patients with impaired microsomal enzyme activity, potentially dangerous.     

Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite

Cytochrome P450 (P450) is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metabolize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are also present in brain where drug metabolism can take place and modify therapeutic action of drugs at the site of action. We have earlier demonstrated an intrinsic difference in the biotransformation of alprazolam (ALP) in brain and liver, relatively more alpha-hydroxy alprazolam (alpha-OHALP) is formed in brain as compared to liver. In the present study we show that recombinant CYP3A43 metabolizes ALP to both alpha-OHALP and 4-hydroxy alprazolam (4-OHALP) while CYP3A4 metabolizes ALP predominantly to its inactive metabolite, 4-OHALP. The expression of CYP3A43 mRNA in human brain samples correlates with formation of relatively higher levels of alpha-OH ALP indicating that individuals who express higher levels of CYP3A43 in the brain would generate larger amounts of alpha-OHALP. Further, the expression of CYP3A43 was relatively higher in brain as compared to liver across different ethnic populations. Since CYP3A enzymes play a prominent role in the metabolism of drugs, the higher expression of CYP3A43 would generate metabolite profile of drugs differentially in human brain and thus impact the pharmacodynamics of psychoactive drugs at the site of action.     

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.     

Dose-dependent inhibition of cyclosporine metabolism in mice by fluconazole

Fluconazole, a potent bis-triazole antimycotic drug, has been demonstrated to inhibit antipyrine metabolism, a cytochrome P-450 dependent process, in vivo in mice. Cyclosporine is metabolized by the cytochrome P-450 enzyme system in both mice and man. We investigated whether fluconazole had any effects on the metabolism of cyclosporine in vivo in mice. The effects of three different doses of fluconazole (1, 5, and 20 mg/kg) on the metabolism of cyclosporine in CD-1 mice were studied in single-dose experiments. Fluconazole produced significant dose-dependent decreases in the elimination rate constant and increases in the terminal half-life of cyclosporine. The 1 mg/kg dose caused a 26% prolongation of the terminal half-life and the 5 and 20 mg/kg dose prolonged the half-life by 72 and 187%, respectively. Fluconazole doses in the 1-5 mg/kg range are effective in mouse models of fungal infections. These results provide further in vivo evidence that fluconazole is a potent inhibitor of the cytochrome P-450 dependent enzyme system in mice. Future experimental studies in animals and humans are needed to evaluate possible metabolic drug-drug interactions involving fluconazole.     

Polymorphism of carbon oxidation of drugs and clinical implications.

Eight volunteers previously phenotyped for their ability to hydroxylate debrisoquine (four extensive metabolisers (EM), four poor metabolisers (PM) were investigated for their metabolic handling of guanoxan and phenacetin. All three drugs are oxidised at carbon centres. Oxidative dealkylation of phenacetin was determined by measuring the rate of formation of paracetamol. The EM subjects excreted mostly metabolites of guanoxan (mean 29% of dose), whereas the PM group excreted large amounts of unchanged drug (48% of dose). The rate of formation of paracetamol was noticeably slower in the PM group, and, when analysed by minimum estimates of apparent first-order rate constants, the difference between the two phenotypes was significant. Thus the hydroxylation defect shown for debrisoquine metabolism carries over to the oxidative metabolism of phenacetin and guanoxan. Some 5% of the population are genetically defective hydroxylators of drugs. Thus methods for evaluating the metabolism of new drugs in respect of usage and side effects need to be revised.     

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.     

Comparative pharmacokinetics of three non-steroidal anti-inflammatory drugs in five bird species

Information on the pharmacokinetics and pharmacodynamics of anti-inflammatory drugs in birds is scarce. Choice of drug and of dosage is usually empirical, since studies of anti-inflammatory drugs are lacking. In this study, three common veterinary non-steroidal anti-inflammatory drugs (NSAIDs) were administered intravenously to five different bird species. Sodium salicylate, flunixin and meloxicam were selected as anti-inflammatory drugs. These NSAIDs were administered intravenously to chickens (Gallus gallus), ostriches (Struthio camelus), ducks (Anas platyrhynchos), turkeys (Meleagris gallopavo) and pigeons (Columba livia). Plasma concentrations of the drugs were determined by validated high-performance liquid chromatography methods and pharmacokinetic parameters were calculated. Most bird species exhibited rapid elimination of these drugs. Ostriches had the fastest elimination rate for all three NSAIDs, but there were some interesting species differences. Chickens had a half-life that was approximately 10-fold as long as the other bird species for flunixin. The half-life of chickens and pigeons was three-fold as long as the other bird species for meloxicam, and, for salicylic acid, the half-life in pigeons was at least three-five-fold longer than in the other bird species.     

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.     

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.     

CYP2D6 polymorphisms in patients with porphyrias

The cytochrome P-450 (CYP) isoenzymes, a superfamily of heme proteins which are the terminal oxidases of the mixed function oxidases system, metabolize more than 70% of all clinically approved drugs. The highly polymorphic CYP2D6 isoform metabolizes more than 25% of most common drugs, and the phenotypes of the 70-plus allelic variants range from compromised to excessive enzymatic activity. Porphyrias are a group of inherited or acquired metabolic disorders of heme biosynthesis, due to a specific decrease in the activity of one of the enzymes of the heme pathway. Clinical signs and symptoms of porphyrias are frequently associated with exposure to precipitating agents, including clinically approved drugs. CYP enzymes, including CYP2D6, participate in the metabolism of some porphyrinogenic drugs, leading to the deregulation of heme biosynthesis. Considering that some of the drugs not recommended for use in porphyric patients are metabolized by CYP2D6, the presence of CYP2D6 polymorphisms in porphyric patients would influence the triggering of the disease when these individuals receive a precipitating agent that is metabolized by CYP2D6. To investigate CYP2D6 polymorphisms in porphyric patients, healthy Argentinean volunteers, porphyric patients, and a group of individuals with high levels of iron were studied. Results indicated that the CYP2D6*3 and CYP2D6*4 alleles, in particular, would be linked to the onset of disease. Predictive genotyping for CYP2D6 in porphyric patients holds promise as a method to improve the clinical efficacy of drug therapy and to personalize drug administration for these patients.     

Changes in Plasma γ-Glutamyl Transpeptidase Activity Associated with Alterations in Drug Metabolism in Man

A significant rise in plasma γ-glutamyl transpeptidase activity (GGT) was observed on 13 out of 14 occasions on which patients on long-term treatment with the oral anticoagulant warfarin were given amylobarbitone, quinalbarbitone, or phenazone (antipyrine) for 30 days. In 13 of these 14 studies there was evidence that drug administration had stimulated the rate of warfarin metabolism. One patient showed no increase in plasma GGT activity, yet a significantly increased rate of warfarin metabolism, and another patient showed an increase in plasma GGT activity without a change in warfarin metabolism. When alterations in both plasma GGT activity and plasma warfarin concentration occurred together in response to drug administration the changes followed a similar time course, occurring after about one week of drug administration with maximal changes at about 10 or 15 days. Administration of chlordiazepoxide, diazepam, nitrazepam, and methaqualone did not stimulate the rate of warfarin metabolism in four patients studied, but plasma GGT activity increased significantly in two of these four instances. The implications of these observations in the interpretation of plasma GGT activities are discussed.     

Kinetics of uptake, clearance, transfer, and metabolism of hexaflumuron by eastern subterranean termites (Isoptera: Rhinotermitidae)

The rates of uptake, clearance, insect-to-insect transfer, and metabolism of [14C] hexaflumuron [N-(((3,5-dichloro-4-(1,1,2,2-tetrafluroethoxy)phenyl)- amino)carbonyl)-2,6-diflurobenzamide] were measured in eastern subterranean termite workers, Reticulitermes flavipes (Kollar), fed cellulose diets containing either 0.1 or 0.5% (wt:wt) hexaflumuron. The rate of uptake, level of maximum uptake, and amount of insect-to-insect transfer were concentration dependent. The clearance rate constant for hexaflumuron was independent of concentration, with a mean value of 3.2 x 10(-3)/h. This corresponds to a mean half-life for hexaflumuron inside termites of 9 d. No evidence of metabolism of hexaflumuron to additional products was detected when extracting and examining the radioactivity contained in the fecal and regurgitated material within the termite holding apparatus 40 d after exposure to the chemical. Hexaflumuron was efficiently transferred from treated to untreated termites, through trophallaxis, resulting in spread of the toxicant throughout the insect population. The combination of uptake and efficient transfer of hexaflumuron between treated and untreated termites ensures broad distribution of the material even to insects not directly exposed to the toxicant. The distribution of hexaflumuron by termite workers, along with their minimal ability to metabolize the compound to other metabolites, and their slow ability to clear the material from the termite population results in death of the entire group of termites contained within the holding apparatus.     

125I-radioimmunoassay for antipyrine

A radioimmunoassay (RIA) for the determination of antipyrine directly in plasma and saliva has been developed using 4-¹²⁵I-iodoantipyrine as the radioligand. The method showed excellent agreement (r=0.98) with a recently reported RIA for antipyrine using ³H-antipyrine as the radioligand. The interassay coefficient of variation for the ¹²⁵I-RIA did not exceed 7.6% and the mean recovery of antipyrine added to plasma or saliva was 101±1.73 (S.E.) over a range of 1.5 to 30 μg/ml. By virtue of its simplicity and low cost, the ¹²⁵I-RIA for antipyrine offers an attractive method for the routine determination of antipyrine levels and subsequent calculation of its half-life in man.     

Urinary cyclophosphamide excretion and micronuclei frequencies in peripheral lymphocytes and in exfoliated buccal epithelial cells of nurses handling antineoplastics

In this study, urinary cyclophosphamide (CP) excretion rate, as well as micronuclei (MN) in peripheral lymphocytes and in buccal epithelial cells were determined for 26 nurses handling antineoplastics and 14 referents matched for age and sex. In urine samples of 20 out of 25 exposed nurses CP excretion rate was found in a range of 0.02-9.14 microg CP/24 h. Our results of the analyses of CP in urine demonstrates that when the nurses were handling CP (and other antineoplastic drugs) this particular compound was observed in urine. The mean values (+/-SD) of MN frequencies (%) in peripheral lymphocytes from the nurses and controls were 0.61 (+/-0. 32) and 0.28 (+/-0.16), respectively (p<0.01). The mean value (+/-SD) of MN frequency (%) in buccal epithelial cells of nurses was 0.16 (+/-0.19) and also mean MN frequency in buccal epithelial cells for controls was found to be as 0.08 (+/-0.08), (p>0.05). Age, sex and smoking habits have not influenced the parameters analyzed in this study. Handling time of antineoplastics, use of protective equipment and handling frequency of drugs have no effect on urinary and cytogenetic parameters analyzed. No correlation was found between the urinary CP excretion and the cytogenetic findings in nurses. Neither could we find any relationship between two cytogenetic endpoints. Our results have identified the possible genotoxic damage of oncology nurses related to occupational exposure to at least one antineoplastic agent, which is used as a marker for drug handling. As a whole, there is concern that the present handling practices of antineoplastic drugs used in the several hospitals in Ankara will not be sufficient to prevent exposure.     

Altered drug metabolism in parasitic diseases

While the immune system represents the main line of host defence against parasite infections, mixed function oxidase (MFO) systems (Box 1) offer the main line of defence against drugs and other biologically active substances. But, as this review shows, many parasites can exert a profound effect on the host MFO system by altering the microsomal drug-metabolizing enzymes and electron transport carriers such as cytochrome P-450. This can markedly affect the host's ability to metabolize biologically active compounds, often with adverse physiological, pharmacological and toxicological consequences. In mammals, drug metabolism occurs predominantly in the liver, and to a lesser extent in the spleen, lungs, kidneys, intestine and cerebral tissues. Thus those parasites that occupy sites in these tissues - such as amoebae, Fasciola, schistosomes and malaria - tend to be those with greatest effects on the host's ability to metabolize drugs. The effects can modify the host response to substances unrelated to the infection, and to drugs which may be administered under a chemotherapeutic regime.     

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.