Decrease In Drug Metabolism Research Articles

Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis

SummaryTryptophan biosynthesis represents an important potential drug target for new anti-TB drugs. We identified a series of indole-4-carboxamides with potent antitubercular activity. In vitro, Mycobacterium tuberculosis (Mtb) acquired resistance to these compounds through three discrete mechanisms: (1) a decrease in drug metabolism via loss-of-function mutations in the amidase that hydrolyses these carboxamides, (2) an increased biosynthetic rate of tryptophan precursors via loss of allosteric feedback inhibition of anthranilate synthase (TrpE), and (3) mutation of tryptophan synthase (TrpAB) that decreased incorporation of 4-aminoindole into 4-aminotryptophan. Thus, these indole-4-carboxamides act as prodrugs of a tryptophan antimetabolite, 4-aminoindole.

The Effect of Polymorphisms in the CYP2D6 and CYP2C9 Genes on the Clinical Efficacy of Tramadol and Ketorolac When Using the Accelerated Recovery Protocol in Patients With Uncomplicated Acute Calculous Cholecystitis Who Underwent Cholecystectomy

Relevance. One of the key components of the accelerated recovery protocols (ARP), in addition to minimizing the surgical approach, is an adequate postoperative analgesia. Despite this, applied postoperative analgesia combinations are not devoid of drawbacks, such as lack of effective postoperative analgesia and the presence of side effect. The use of a pharmacogenetic approach to analgesic therapy for the purpose of its personalization may increase the effectiveness and safety of the use of analgesics. In particular, the presence of an inactive CYP2D6*4 allele , in which the conversion of tramadol to its active metabolite is reduced, contributes to the insufficient efficacy of the drug. As for non-steroidal anti-inflammatory drugs, the presence of CYP2C9*2/*3 polymorphisms leads to a decrease in drug metabolism and a longer half-life, resulting in the increase of the clinical effect and the risk of adverse reactions. Thus, genotyping of patients with the determination of the presence of specific genetic factors can rationalize the postoperative analgesia.Aim of study. Evaluation of the possible association of polymorphisms of the CYP2D6 and CYP2C9 genes with the clinical efficacy of tramadol and ketorolac in relation to postoperative pain.Material and methods. This observational clinical study involved 107 patients with uncomplicated acute calculous cholecystitis who underwent videolaparoscopic cholecystectomy and perioperative treatment according to ARP. All patients underwent whole blood sampling followed by real-time polymerase chain reaction genotyping. Analgesic efficacy was assessed using a visual analog scale (VAS) and McGill Pain Questionnaire.Results. In CYP2D64* carriers pain was higher than that of wild-type carriers, according to VAS and McGill Pain Questionnaire in all investigated periods. In carriers of CYP2C9*2, the pain syndrome was lower than in carriers of the wild type at all intervals studied. In carriers of CYP2C9*3 pain was lower only after 2 and 6 hours, also according to McGill Pain Questionnaire.Conclusion. 1. The presence of the polymorphic marker CYP2D6*4 may reduce the efficacy of postoperative tramadol analgesia compared with wild type. 2. The presence of the polymorphic marker CYP2C9*2 and CYP2C9*3 may increase the efficacy of ketorolac pain relief compared to wild type.

Resistance of Mycobacterium Tuberculosis to Indole 4-Carboxamides Occurs Through Alterations in Drug Metabolism and Alterations in Tryptophan Biosynthesis

Tryptophan biosynthesis represents an important potential drug target for new anti-TB drugs. We identified a series of indole-4-carboxamides with potent antitubercular activity. In vitro, Mycobacterium tuberculosis (Mtb) acquired resistance to these compounds through three discrete mechanisms: (1) a decrease in drug metabolism via loss-of-function mutations in the amidase that hydrolyses these carboxamides, (2) an increased biosynthetic rate of tryptophan precursors via loss of allosteric feedback inhibition of anthranilate synthase (TrpE), and (3) mutation of tryptophan synthase (TrpAB) that decreased incorporation of 4-aminoindole into 4-aminotryptophan. Thus, these indole-4-carboxamides act as prodrugs of a tryptophan antimetabolite, 4-aminoindole.

Downregulation of hepatic acetylation of drugs in chronic renal failure.

Drug metabolism can be affected by chronic renal failure (CRF). Although it is known that several drugs that are known to be acetylated accumulate in CRF, the effect of CRF on N-acetyltransferase (NAT), the enzyme responsible for this acetylation, is unknown. Herein is reported that protein and gene expression of both Nat isoforms in the liver was reduced by >30% and Nat2 activity was reduced by 50% in rats with CRF compared with control rats. Incubation of hepatocytes with serum from rats with CRF suggested that a circulating factor is responsible for the decrease in protein and gene expression. For testing the hypothesis that parathyroid hormone may be this factor, CRF was induced in parathyroidectomized rats; downregulation of Nat expression and activity was not observed in these rats. Furthermore, addition of parathyroid hormone to cultured hepatocytes induced a decrease in Nat2 protein and gene expression. In conclusion, liver acetylation of drugs in a rat model of CRF is reduced by a downregulation of Nat1 and Nat2 isoforms, secondary to decreased gene expression. Parathyroid hormone seems to be an important mediator of this phenomenon.

A Comparative Study of Three Warming Interventions to Determine the Most Effective in Maintaining Perioperative Normothermia

A Comparative Study of Three Warming Interventions to Determine the Most Effective in Maintaining Perioperative Normothermia

Plasma levels of TNF-α and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure

Background: Cytochrome P450 (CYP) enzymes are important mediators of drug metabolism, and activity of these enzymes is a major determinant of the duration and intensity of drug effect. Circulating plasma concentrations of pro-inflammatory cytokines (e.g., tumor necrosis factor [TNF]-α and interleukin [IL]-6) are elevated in patients with heart failure and these cytokines have been shown to down-regulate CYP enzyme activity. The purpose of this study was to evaluate the relationship between plasma cytokine concentrations and CYP enzyme activities in patients with heart failure. Methods and Results: Sixteen patients with congestive heart failure (New York Heart Association classes II-IV) received a metabolic probe cocktail consisting of caffeine, mephenytoin, dextromethorphan, and chlorzoxazone to assess the activities of the CYP enzymes 1A2, 2C19, 2D6, and 2E1. Blood and urine samples were collected for drug and metabolite determinations by high-performance liquid chromatography (HPLC); cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA). We found a striking inverse relationship between both TNF-α and IL-6 plasma concentrations and the activity of CYP2C19; metabolism of caffeine (CYP1A2) also had a negative association with IL-6 plasma concentrations. Conclusions: Cytokine-mediated decreases in drug metabolism may contribute to observed variability in drug response and augment the risk of adverse drug effects in CHF patients.

Downregulation of hepatic cytochrome P450 in chronic renal failure.

Chronic renal failure (CRF) is associated with a decrease in drug metabolism. The mechanism remains poorly understood. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYP450). Three groups of rats were defined: control, control paired-fed, and CRF. Total CYP450 activity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver microsomes. The regulation of liver CYP450 by dexamethasone and phenobarbital was assessed in CRF rats. Compared with control and control paired-fed rats, creatinine clearance was reduced by 60% (P: < 0.01) in CRF rats. Weight was reduced by 30% (P: < 0.01) in control paired-fed and CRF rats, compared with control animals. There was no difference in the CYP450 parameters between control and control paired-fed. Compared with control paired-fed rats, total CYP450 was reduced by 47% (P: < 0.001) in CRF rats. Protein expression of CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (>40%, P: < 0.001) in rats with CRF. The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the same in the three groups. Northern blot analysis revealed a marked downregulation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats. Although liver CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbital was present. N-demethylation of erythromycin was decreased by 50% in CRF rats compared with control (P: < 0.001). In conclusion, CRF in rats is associated with a decrease in liver cytochrome P450 activity (mainly in CYP2C11, CYP3A1, and 3A2), secondary to reduced gene expression.

Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions.

The effect of aging on drug metabolism in humans has not yet been completely described. Two hundred twenty-six patients with equal histopathologic conditions were investigated. The cytochrome P450 contents in the liver biopsy samples, the plasma antipyrine clearance rates after oral administration and, as an independent control of vitality, serum testosterone levels were determined. Cytochrome P450 content in subjects from 20 to 29 years of age was 7.2 +/- 2.6 nmol.gm-1, increased during the fourth decade (+7.2%, p = NS), declined after 40 years (-16%, p < 0.01) to a level that remained unaltered up to 69 years, and declined further after 70 years (-32%, p < 0.001). The antipyrine (phenazone) clearance rate in young subjects was 46.4 +/- 18.5 ml.min-1, remained unaltered during the fourth decade, and declined after 40 years by a rate of 0.34 ml.min-1 per year toward old age (-29%, p < 0.001). The half-life in young subjects was 9.5 +/- 2.0 hours and increased after 30 years toward old age (+26%, p < 0.001). The volume of antipyrine distribution, 0.46 +/- 0.12 L.kg-1 in young subjects, decreased after 30 years (-11%). In line with the testosterone content, the decrease in drug metabolism was equal in both sexes. This study shows a reduction of in vitro and in vivo drug metabolism with age in humans. The data suggest that at least three age groups--young, middle-aged, and elderly--should be included in the evaluation of the pharmacokinetics of a new drug. The reduction of drug metabolism (-30%) after 70 years of age indicates that care is needed in the prescription of drugs for elderly subjects.

A mechanism for the loss of cytochrome P-450 in primary mouse hepatocytes

This study examined various biochemical parameters such as mitochondria and mitochondrial DNA (mtDNA), total heme and cyto P450 content in fresh hepatocytes and dedifferentiated hepatocytes. These parameters were chosen in order to understand the dramatic decrease in drug metabolism in cultured hepatocytes. The data in this study shows a temporal decrease in cytochrome P450, a total heme and also a decrease in mitochondria. Also, the ratio of mtDNA content to mitochondrial density was found to increase as hepatocytes underwent dedifferentiation. Stereological analysis of cell preparations provided a measure of mitochondrial density per cell area and mtDNA content was assessed by the use of a specific radiolabelled probe. This study demonstrates that a loss of the organelle which is partially responsible for synthesis of heme correlates with a decrease in cytochrome P450.

Quantitative liver function in the elderly assessed by galactose elimination capacity, aminopyrine demethylation and caffeine clearance

Hepatic function was assessed in 13 healthy elderly subjects, 71-88 years of age, with three quantitative tests of liver function. The galactose elimination capacity was significantly (P less than 0.05) lower in the elderly (6.08 +/- 1.30 mg X min-1 X kg-1, mean +/- SD) than in a group of 70 subjects under 40 (7.48 +/- 0.94 mg X min-1 X kg-1) and 11 subjects between the age of 40 and 70 (7.08 +/- 0.68 mg X min-1 X kg-1). The demethylation of aminopyrine as assessed by the aminopyrine breath test, and the systemic clearance of caffeine, two measures of microsomal function, demonstrated a comparable decrease but showed much more interindividual variation. Caffeine clearance decreased from 1.49 +/- 0.44 ml X min-1 X kg-1 in young adults to 0.97 +/- 0.39 ml X min-1 X kg-1 (P less than 0.01) in the elderly, and the demethylation of aminopyrine decreased from 0.79 +/- 0.15 to 0.62 +/- 0.20% dose X kg X mmol-1 (P less than 0.05). Our data indicate that aging is associated with a loss of the functioning mass of hepatocytes. The decrease in drug metabolism parallels the loss of functional mass but shows more interindividual variation probably reflecting the many genetic and environmental factors influencing these tests of microsomal function.

Influence of age-related changes in rodent liver morphology and physiology on drug metabolism — A review

Age-related changes in weight, morphology and physiology of the rodent liver influencing hepatic drug metabolism are reviewed. Next to the changes in liver weight/body weight ratio with age, the spontaneous occurrence of neoplastic and non-neoplastic lesions may be of particular importance. In addition, the decrease in liver blood blow with age diminishes the biotransformation capacity of the total liver. However, the albumin concentration in plasma and drug uptake do not play important roles, since they are unchanged or only slightly lower in old rats or mice. Drugs are generally metabolized by the liver in two phases: the so-called phase I and phase II metabolism. For most drugs, the phase I reaction is an oxidation. This reaction is catalyzed by cytochrome P-450, cytochrome b 5 and NADPH-cytochrome c reductase. In microsomes, a decrease with age is generally observed in the cytochrome P-450 concentration and the NADPH-cytochrome c reductase activity, while there is no change in cytochrome b 5. In addition, most microsomal drug-metabolizing enzymes decrease with age in male rats but not in females. The changes in enzyme activities in the male and female mouse are more complex. In fact, increases, decreases and no changes were found. Important phase II reactions are glutathione conjugation and glucuronidation; changes in both reactions with age seem to be of minor importance. Studies with hepatocytes isolated from male rats of different ages reveal that the monooxygenase system mediated metabolism of digitoxin and aflatoxin B1 decreases with age. It can be concluded that the observed decrease in the functional capacity of the monooxygenase system greatly determines the decrease in drug metabolism with age. However, it should always be kept in mind that, among others, the age-related changes in drug metabolism in rats are strongly sex dependent, which is not the case in man. Therefore, caution should be exercised in transferring these data to the human situation.

Increasing lipid peroxidation by vitamin E deficiency does not augment adriamycin-induced inhibition of hepatic drug metabolism

Adriamycin treatment in vivo or addition to incubation mixtures in vitro inhibits hepatic drug metabolism. It has been suggested that adriamycin-induced membrane lipid peroxidation may be a mechanism responsible for this activity in vitro. To determine if similar mechanisms operate in vivo, adriamycin inhibition of drug metabolism was compared in rats whose tissue lipid peroxidizability was altered by manipulating dietary levels of vitamin E. Weanling rats maintained on vitamin E deficient (0 ppm) or supplemented (10 or 100ppm) diets for 12 weeks were given either adriamycin, 5 mg/kg/week, or equal volumes of the saline vehicle for 3 weeks intraperitoneally. Vitamin E deficiency alone (0 ppm, saline pretreatment) produced a 37% increase in hepatic lipid peroxidation without any appreciable alteration in hepatic aniline hydroxylase, ethylmorphine N-demethylase or aryl hydrocarbon hydroxylase activities. Adriamycin pretreatment altered hepatic lipid peroxidizability over corresponding saline pretreated controls dependent on dietary vitamin E. No increase was seen in the 100 ppm group, while 44% and 500% increases occurred at 10 and 0 ppm vitamin E, respectively. Adriamycin pretreatment decreased drug-metabolizing enzyme activity by an average of 32% for aniline hydroxylase, 26% for ethylmorphine N-demethylase and 63% for aryl hydrocarbon hydroxylase. Statistically, decreases in drug metabolism were independent of dietary vitamin E and did not correlate with lipid peroxidizability. These data would suggest that in vivo adriamycin-induced depression of hepatic drug-metabolizing enzymes is not mediated by elevated lipid peroxidation.

Drug metabolism in rats with arthritis induced by 6-sulfanilamidoindazole (6-SAI).

Hexobarbital sleeping time was prolonged and ethylmorphine N-demethylation was inhibited after a single dosage or seven administration of 6-SAI to old rats. These effects were independent of the development of arthritis. Changes in cytochrome P-450 concentration after 6-SAI treatment were insignificant and thus not responsible for the decrease in drug metabolism. In vitro 6-SAI inhibited ethylmorphine N-demethylation; the inhibition was of a mixed type. 6-SAI bound to cytochrome P-450 and induced a type II spectrum. The magnitude of hexobarbital-induced type I spectral changes was diminished by 6-SAI. It is concluded that 6-SAI inhibits cytochrome P-450-dependent drug metabolism by binding to cytochrome P-450.

Selenium antagonism of cadmium-induced inhibition of hepatic drug metabolism in the male rat

Experiments were undertaken to examine the effect of selenium, an essential trace element, on cadmium-induced inhibition of drug metabolism in male, Sprague-Dawley derived rats. Prior administration of sodium selenite (1.6 mg Se/kg, ip) blocked the cadmium-induced (0.84 mg Cd/kg, ip) prolongation of hexobarbital-induced hypnosis and inhibition of hepatic microsomal biotransformation of ethylmorphine or aniline. Selenium also blocked cadmium-induced reduction in microsomal cytochrome P-450 content and the microsomal binding of both ethylmorphine and aniline. However, pretreatment of rats with selenium did not prevent the inhibitory effect of cadmium (10 −6 to 10 −3 m) added in vitro on either ethylmorphine or aniline biotransformation. In addition, the reduction in biotransformation of both substrates following in vivo cadmium administration was not reversed following the in vitro administration of selenium but, in fact, selenium produced further concentration-dependent decreases in drug metabolism. In additional in vitro experiments it was found that the inhibition in drug metabolism induced by in vitro additions of cadmium is not affected by similar additions of selenium when added to the incubation vessel either before or after the cadmium. Thus, for selenium to prevent the cadmium-induced inhibition of hepatic drug metabolism requires in vivo administration of selenium.

Hepatic aminopyrine N-demethylase, acetanilide hydroxylase and lipid peroxidation in young growing rats during the treatment of insecticides.

Halogenated hydrocarbon insecticides and their metabolites are knovm to alter the activity of microsomal enzymes(HART et a1.1963, HART and FOUTS 1963, 1965, WELCH et a1.1967, BUNYAn and PAGE 1973). in contrast to the halogenated hydrocarbons there are very few reports regarding the effect of organophosphorus and carbamate insecticides on microsomal drug metabolizing enzymes. Hepatic drug metabolism has been found to be decreased by malathion in mice and rats (STEVENS et al. 1972, RA0 and ANDERS 1973, STEVENS and GREENE 1973). Very recently, STEVENS and GREENE (1974) have showed that subacute administration of insecticides resulted in induction of hepatic drug metabolism and mixed function oxidase systems in rats! however, WEBER et a1,(1974) have reoorted that parathion inhibited the metabolism of benzo(a)pyrene in rat liver and intestine. Our earlier investigations have reported an increase in drug metabolizing enzymes and lipid peroxidation during Take20 administration and a decrease in drug metabolism followed by an increased lipid peroxidation during Baygon administration in young growing rats (MAKHIJA and PAWAR 1974,1975). A literature review indicates a paucity of toxicological data and hence the present experiments were planned to investigate the effect of Take-20 (0,0dimethyl malathion) and Baygon on hepatic drug metabolism and lipid peroxidation in young growing rats.

Altered rat hepatic drug metabolism after implantation of a pituitary mammotropic tumor (MtT), Walker carcinosarcoma or adenocarcinoma and after removal of the MtT.

The liver metabolism of hexobarbital and aminopyrine was studied at various times after implantation and removal of the Furth pituitary mammotropic tumor (MtT). A decrease in liver metabolism of these 2 compounds was noted 12 days after implantation of the MtT, and this decrease was maximum after 20 days of MtT growth. No decrease in hepatic microsomal protein was observed. Enlargement of adrenals, kidneys, liver and a decrease in testicular weight were noted in MtT-bearing animals. No relationship between organ weight changes and the reduction in liver metabolism was observed. Removal of the MtT produced a gradual return in liver drug metabolic enzyme activity to control levels by 16 days. The weight of liver, kidneys, adrenals and testes also returned to normal levels in animals without the MtT, and no relationship between changes in drug metabolism and organ weight was noted. Implantation of 2 tumors of nonpituitary origin, the Hilf adenocarcinoma R3230AC and the Walker carcinosarcoma 256, revealed a decrease in drug metabolism which occurred in rats with large tumors. This decrease was related to tumor mass, but no such relationship was established for animals with the MtT. Pituitary hormones produced by the MtT probably affect hepatic drug metabolism, and this accounts for a lack of similarity between the effect of this tumor on drug metabolism as compared with 2 tumors of nonpituitary origin. These time course studies with the MtT support the hypothesis that small amounts of pituitary hormones from a grossly undetectable tumor mass decreased hepatic microsomal drug metabolism in the rat. (Endocrinology88: 185, 1971)