Studies on drug metabolism. XI. Metabolic interaction of aniline and phenylbutazone on the liver microsomal drug metabolizing enzymes.
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Aniline Compounds↗
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Metabolic interactions of putative cytochrome P4503A substrates with alternative pathways of dapsone metabolism in human liver microsomes.
The cytochrome P4503A (CYP3A) subfamily of enzymes are responsible for the metabolism of a large number of endogenous and exogenous compounds, and activation of some procarcinogens; but the activity is not well understood. N-Hydroxylation of dapsone in human liver microsomes has been shown to be mediated largely by CYP3A4. We have also observed the formation of an as yet unidentified metabolite of dapsone, whose formation is inhibited by antibody to CYP3A4, by these microsomes. This study investigated the influence of various (22) CYP3A putative substrates on the formation of both metabolites of dapsone in human liver microsomes. The compounds fall into four different categories on the basis of the pattern of their inhibitory interaction with the formation of both metabolites: those that inhibited both metabolites; those that inhibited N-hydroxylamine alone; those that inhibited the unidentified metabolite alone; and those with no significant effect on either metabolite. Some others were stimulatory. These results are consistent with two alternative but not mutually exclusive hypotheses: 1) different isoforms of CYP3A are involved in the formation of the alternative metabolites and the pattern of interaction observed was caused by the particular isoform(s) that each compound interacted with; or 2) formation of the alternative metabolites is a result of dapsone's interaction with and orientation at the enzyme's active site and the pattern of interaction observed is a consequence of changes in orientation caused by these compounds. This study provides relevant observations that must be considered in understanding mechanisms of CYP3A-mediated metabolism.
Catalysis↗
Tumour-host metabolic interaction and cachexia.
Cachexia is a terminal metabolic problem observed in a wide variety of tumours. In this article I propose that the syndrome is a direct consequence of the common feature to all malignant tumours: growth. I suggest that the requirement for essential amino acids can be used as the unifying principle that links the tumour to the two main components of cachexia: muscle wastage and anorexia. This underlying factor is usually clouded by the overlapping of individual tumour characteristics.
Amino Acids↗
Metabolic interactions between surplus dietary energy intake and cigarette smoking or its cessation.
Cigarette smoking (CS) alters lipid metabolism and is associated clinically with an atherogenic lipid profile. We recently showed that, under controlled eucaloric dietary conditions, CS stimulates lipolysis without increasing oxidation of fat and that cessation of CS does not result in a rebound tendency to synthesize or store fat. We asked here whether the ad libitum intake of surplus dietary energy interacts with the metabolic effects of CS or its cessation. Eight male heavy smokers were allowed ad libitum food intake in a metabolic ward, 1 wk in CS phase and 1 wk in non-CS phase, followed by 4 wk of outpatient non-CS and a repeat 7-day study. De novo hepatic lipogenesis (DNL), lipolysis, substrate cycling of free fatty acids (FFA), hepatic glucose production, and energy expenditure were measured by using a multiple stable-isotope infusion protocol and indirect calorimetry. Surplus dietary energy intake (> 150% of predicted energy needs) occurred in five of eight subjects (2 subjs > 5,500 kcal/day, 3 subjs > 4,000 kcal/day) with weight gain of 1-4 kg/wk, but with no difference between CS and non-CS phases. Acute CS significantly increased (P < 0.05) serum FFA concentrations (58%), FFA flux (63%), and glycerol flux (36%); nonsignificantly increased extra-adipocyte (hepatic) esterification of FFA (125%, P = 0.10) and resting energy expenditure (4.1%, P = 0.22); and did not change adipocyte reesterification of FFA or whole body oxidation of fat. Basal metabolic parameters (after overnight abstention from CS) did not differ between phases. Fractional DNL correlated significantly with excess energy intake (r2 = 0.39) and with percentage of total energy needs provided by carbohydrate (r2 = 0.47). The absence or presence of CS did not affect the increase in fractional DNL in subjects with excess energy intake, however. We conclude that cessation of CS does not result in a rebound tendency to synthesis or storage of fat, even in the presence of positive short-term energy balance, contrary to previous suggestions. Moreover, stimulation of lipolysis by CS does not increase oxidation of fat and thereby protect against fat deposition under conditions of surplus energy intake. The prevention of weight gain after cessation of CS, whether or not nicotine is provided, should focus on energy balance (calorigenesis as well as intake) rather than specific alterations in lipid metabolism.
Adult↗
Probable metabolic interaction between methadone and fluvoxamine in addict patients.
We report five cases where fluvoxamine (FLVX) was added to maintenance treatment with methadone (MTD) in addict patients with affective disorders. In view of the implication of FLVX in several metabolic drug interactions, MTD plasma levels were measured before and after treatment with FLVX. A slight increase (approximately 20% of the MTD plasma level/dose ratio) occurred in two cases. In the remaining three patients, the interaction was more pronounced (40-100% increase of the MTD plasma level/dose ratio), with clinical manifestations of opiate withdrawal after stopping FLVX therapy in one case. Caution is needed when starting or stopping treatment with FLVX in patients receiving maintenance treatment with methadone.
Adult↗
Metabolic interaction of ethanol and cyclohexanone in rabbits.
The interaction of ethanol (EtOH) and cyclohexanone (CHN) metabolism was studied to demonstrate the influence of alcohol beverage in cyclohexanone poisoning. Rabbits were administered CHN and EtOH separately or together, and the plasma concentration of CHN and cyclohexanol (CHL), a metabolite of CHN, and blood concentrations of EtOH were measured at various times. When CHN alone was administered orally, the time to maximum plasma concentration (Tmax) of CHN was as short as 15 min, but that of CHL was 120 min. The short Tmax of CHN was considered to be due to the first-pass effect. The plasma concentration of CHL was much greater than that of CHN. On the other hand, when the same amount of molar CHL was administered in rabbits for sake of comparison, only small amounts of CHN were detected in plasma. The interconversion between CHN and CHL at the time of equilibration tended to shift predominantly toward the formation of CHL, whose plasma concentration ratio was about 1:6 to 1:8. The coadministration of EtOH decreased the plasma concentration of CHN and increased that of CHL more than the administration of CHN alone. The blood concentration of EtOH was also decreased with the coadministration of CHN. The coadministration of EtOH with CHN demonstrated an acceleration in the metabolism of both CHN and EtOH, which may be due to an increase in the concentrations of the alcohol dehydrogenase-NADH and -NAD complexes.
Administration, Oral↗
Metabolic interactions of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole with other drugs.
PURPOSE: To analyse the metabolism of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole by cytochrome P450 (CYP) enzymes, and to assess the consequences for drug-drug interactions. RESULTS OF DATA ANALYSIS: Lansoprazole, omeprazole and pantoprazole are extensively metabolized by several human cytochromes P450, most prominently by mephenytoin hydroxylase (CYP2C19) and nifedipine hydroxylase (CYP3A4). Only pantoprazole is also metabolized to a significant extent by a conjugating enzyme, a cytosolic sulfotransferase. The substrates and inhibitors of CYP2C19 and CYP3A4 and the known genetic polymorphism of CYP2C19 explain some but not all of the interactions of lansoprazole, and particularly the interactions of omeprazole with carbamazepine, diazepam, phenytoin and theophylline or caffeine. Both lansoprazole and omeprazole apparently also induce cytochromes P450 such as CYP1A2. This effect appears at lower doses of omeprazole in poor metabolizers of omeprazole. Of these three drugs, pantoprazole has by far the lowest potential for interactions, both in vitro (in microsomal studies) and in volunteer studies. CONCLUSIONS: Proton-pump inhibitors interact with and are metabolized by several human cytochromes P450, but only pantoprazole is also metabolized by a sulfotransferase. This may partly explain why, in this group of proton-pump inhibitors, pantoprazole has the lowest potential for interactions with other drugs.
2-Pyridinylmethylsulfinylbenzimidazoles↗
[Nucleo-cytoplasmatic metabolic interactions].
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Cell Biology↗
Metabolic interactions of glucagon and cortisol in man--studies with somatostatin.
The metabolic response to pathophysiologic concentrations of glucagon, induced by glucagon infusion, has been examined in normal man before and after 36-60 hr hypercortisolaemia, induced by administration of tetracosactrin-depot. Glucagon alone increased serum insulin levels twofold but blood glucose was unaltered. Plasma NEFA and blood ketone body concentrations were decreased by glucagon infusion. Tetracosactrin produced a threefold rise in serum cortisol levels and caused mild fasting hyperglycemia and hyperinsulinaemia. Subsequent glucagon infusion had no effect on circulating insulin, glucose, NEFA or ketone body concentrations. Simultaneous infusion of somatostatin, to produce partial insulin-deficiency, unmasked a hyperglycemic action of glucagon (+ 3.8 +/- 0.2 mmol/l at 90 min, p less than 0.02). This glucagon-induced rise in blood glucose was diminished by prior tetracosactrin administration. Tetracosactrin revealed a mild lipolytic action of glucagon in partial insulin deficiency, not apparent in the euadrenal state. Glucagon was equally hyperketonemic during somatostatin infusion before and after tetracosactrin. Thus the hyperglycemic and hyperketonemic actions of glucagon at pathophysiologic levels are restricted to insulin deficiency. Hypercortisolaemia reveals a lipolytic action of glucagon in insulin-deficient man but does not potentiate the hyperglycemic or hyperketonemic effects.
Adult↗
[The metabolic interactions between Paramecium bursaria Ehrbg. and Chlorella spec. in the Paramecium bursaria-symbiosis. I. The nitrogen and the carbon metabolism (author's transl)].
Symbiotic Chlorellae have been isolated from Paramecium bursaria Ehrbg. and cultivated under conditions of nitrogen deficiency. Reinfection of Chlorella-free Paramecium bursaria with these nitrogen-deficient algae resulted in a complete regeneration and multiplication of the algae within the host cells. The endosymbiotic algal cells of the Paramecium bursaria-symbiosis can be supplied by their host with nitrogen. The inhibition of photosynthesis by 3-(3,4-Dichlorophenyl)-1,1-dimethylurea (DCMU) leads in green Paramecium bursaria to a breakdown of the symbiotic steady state-system resulting in a loss of algal cells. Obviously the endosymbiotic algae cannot be fed heterotrophically by their host to such an extent that a stable symbiosis is maintained. The application of 3-(3,4-Dichlorophenyl)-1,1-dimethylurea (DCMU) can be used as a new method for culturing Chlorella-free Paramecium bursaria.
Chlorella↗
Cimetidine-methylprednisolone-theophylline metabolic interaction.
The pharmacokinetics of theophylline and methylprednisolone were examined before and during cimetidine treatment in an asthmatic woman who required long-term administration of these drugs. Cimetidine reduced theophylline plasma clearance by 30 percent, and measurement of urinary metabolites showed that 3-methylxanthine formation was inhibited more strongly than that of the methylated uric acid metabolites. Assessment of methylprednisolone disposition following oral and intravenous doses revealed no effect of cimetidine on the bioavailability (74 to 81 percent absorption) or plasma clearance (22 to 24 liters per hour) of the steroid. Thus, cimetidine exhibits variable and selective effects on the biotransformation pathways of drugs important in asthma therapy.
Adult↗
Cerebral metabolic interactions between thyroid state and imipramine in the rat.
Local rates of cerebral glucose metabolism were determined in four groups of adult rats 4 weeks after surgery: sham-operation + saline; thyro-parathyroidectomy (TX) + saline; sham-operation + imipramine; or TX + imipramine. Daily i.p. injections, imipramine at 10 mg/kg or saline at 1 ml/kg b.w., were given during the 2 weeks before the deoxyglucose experiment. TX reduced glucose utilization in the limbic, motor, endocrine and auditory systems. Imipramine reduced glucose metabolism in the median eminence, both habenular nuclei and several limbic regions including the amygdala, hippocampus and parietal cortex. Five structures showed significant interactions between TX and imipramine. In three of these regions, the supraoptic nucleus, central amygdala and lateral habenula; TX and/or imipramine individually reduced metabolism and the combined treatment raised it back to within the normal range. In the dorsal raphe, TX and imipramine tended to increase metabolism and the combined treatment resulted in a decrease to within normal range. The neurohypophysis, unaffected by TX alone, showed a significant increase in activity when TX was combined with imipramine. These data indicate, in part, that both hypothyroidism and imipramine treatment alone depress metabolism in limbic forebrain and the major limbic-brainstem relay nuclei. Combined treatment normalizes metabolism in many of these limbic pathways. Hypothetically, hypothyroidism may alter central catecholamine function in such a way that the metabolic response to imipramine is reversed or altered.
Animals↗
Human metabolism and metabolic interactions of deployment-related chemicals.
It has been suggested that chemicals and, more specifically, chemical interactions, are involved as causative agents in deployment-related illnesses. Unfortunately, this hypothesis has proven difficult to test, because toxicological investigations of deployment-related chemicals are usually carried out on surrogate animals and are difficult to extrapolate to humans. Other parts of the problem, such as the definition of variation within human populations and the development of methods for designating groups or individuals at significantly greater risk, cannot be carried out on surrogate animals, and the data must be derived from humans. The relatively recent availability of human cell.fractions, such as microsomes, cytosol, etc., human cells such as primary hepatocytes, recombinant human enzymes, and their isoforms and polymorphic variants has enabled a significant start to be made in developing the human data needed. These initial studies have examined the human metabolism by cytochrome P450, other phase I enzymes, and their isoforms and, in some cases, their polymorphic variants of compounds such as chlorpyrifos, carbaryl, DEET, permethrin, and pyridostigmine bromide, and, to a lesser extent, other chemicals from the same chemical and use classes, including solvents, jet fuel components, and sulfur mustard metabolites. A number of interactions at the metabolic level have been described both with respect to other xenobiotics and to endogenous metabolites. Probably the most dramatic have been seen in the ability of chlorpyrifos to inhibit not only the metabolism of other xenobiotics such as carbaryl and DEET but also to inhibit the metabolism of steroid hormones.
Drug Interactions↗
Metabolic interactions of central nervous system medications and selective serotonin reuptake inhibitors.
Selective serotonin reuptake inhibitors (SSRIs) are prescribed alone and in combination with other psychotropic medications in the treatment of a variety of psychiatric disorders. Such combinations create the potential for pharmacokinetic interactions by affecting the activity of the cytochromes P450 (CYP450), drug metabolizing oxidative enzymes. SSRIs are not equivalent in their potential for interactions when combined with other central nervous system (CNS) medication. Generally citalopram and sertraline are characterized by weaker inhibition of CYP450 enzymes and, therefore, hold less potential for interaction than the other SSRIs. Paroxetine potently inhibits CYP2D6, which can result in increased neuroleptic serum concentrations, accompanied by increased CNS side-effects. Similarly, as a potent inhibitor of CYP2D6, fluoxetine can increase serum concentrations of neuroleptics and antidepressants and numerous case reports have documented concomitant adverse events. Fluoxetine also inhibits CYP3A and CYP2C19, increasing serum concentrations of some benzodiazepines. Fluvoxamine is a potent inhibitor of CYP1A2, a moderate inhibitor of CYP3A and a mild inhibitor of CYP2D6. Therefore, interactions with clozapine and benzodiazepines are evident.
Animals↗
The stimulus-secretion coupling of amino acid-induced insulin release. Metabolic interaction of L-glutamine and 2-ketoisocaproate in pancreatic islets.
1. The metabolic situation found in pancreatic islets exposed to both L-glutamine and 2-ketoisocaproate was investigated in order to assess its relevance to the synergistic effects of these nutrients upon insulin release. 2. In islet homogenates, serveral 2-keto acids could be used as partners for the transamination of L-glutamate to 2-ketoglutarate. The rate of transamination did not correlate positively with the capacity of each 2-keto acid to stimulate insulin release in the presence of L-glutamine. 3. L-Glutamine enhanced the production of L-leucine from 2-ketoisocaproate and inhibited the conversion of the 2-keto acid to acetoacetate and CO2. L-Glutamine also inhibited the oxidation of pyruvate. 4. In the presence of 2-ketoisocaproate, the rate of generation of 2-ketoglutarate from exogenous L-glutamine was increased, but the oxidative deamination of glutamate was suppressed. 5. L-Valine antagonized the effect of 2-ketoisocaproate to augment 14CO2 output from islets prelabelled with L-[U-14C]glutamine. 6. L-Glutamine did not increase the islet content of reduced pyridine nucleotides beyond the high level reached in the sole presence of 2-ketoisocaproate. 7. If allowance was made for the influence of exogenous nutrients upon the oxidation of endogenous nutrients, the insulin output evoked by L-glutamine and/or 2-keto acids tightly depended on the increment in oxidation rate attributable to these nutrients. 8. The metabolic and secretory responses to L-glutamine and 2-ketoisocaproate were best explained by a stimulation of transamination reactions between 2-ketoisocaproate and glutamate derived from exogenous glutamine.
Animals↗
Metabolism of acetate in rat brain neurons, astrocytes and cocultures: metabolic interactions between neurons and glia cells, monitored by NMR spectroscopy.
The existence of metabolic compartmentation is generally accepted for the brain because of the specific differences in glial and neuronal metabolism. Extracellularly supplied acetate is believed to serve as a substrate only for glia cells, but not for neurons. To further test this hypothesis, primary rat brain cultures of neurons, astrocytes, and cocultures of both cell types were used to investigate the metabolic fate of [2-13C]acetate by means of nuclear magnetic resonance (NMR) spectroscopy. Acetate was metabolized by both cell types, neurons and astrocytes in culture. While glutamine was the main product of glial metabolism, labelled glutamate and aspartate were detected in neuron cultures. Astrocytes and neurons in cocultures showed a very different picture, which is similar to results obtained from brain slices, or in vivo studies. The analysis of the isotopomer pattern of glutamate and glutamine confirm an active glutamate-glutamine-cycle between neurons and astrocytes in cocultures. Furthermore, the analysis of unlabelled metabolites revealed a metabolic coupling of hypotaurine and taurine metabolism in astrocytes and neurons, which provides both cell types with one of the most important organic osmolytes.
Acetates↗
Metabolic interactions of ciprofloxacin.
The mechanism and clinical relevance of the inhibitory effect of ciprofloxacin on the metabolism of selected drugs were studied in patients with bacterial infections. In study A, antipyrine tests were carried out in two groups of patients taking 1000 mg (group 1) and 250 mg (group 2) of oral ciprofloxacin for 7-10 days. Antipyrine was given intravenously in a dose of 15 mg/kg body weight before and after ciprofloxacin treatment. Blood samples were taken at 0, 2, 4, 6, and 10 hr after dosing. In group 1, ciprofloxacin administration resulted in a significant decrease in antipyrine elimination (t1/2, 9.45 +/- 3.74 vs. 14.92 +/- 3.32 hr). The average decrease in antipyrine clearance was 35% (0.85 +/- 0.45 vs. 0.52 +/- 0.24 ml/min/kg). In group 2, the change in antipyrine kinetics was less pronounced (t1/2, 9.79 +/- 3.06 vs. 11.22 +/- 2.64 hr). Antipyrine clearance was decreased by only 10% (0.77 +/- 0.13 vs. 0.70 +/- 0.14 ml/min/kg). These results support the hypothesis that ciprofloxacin inhibits the oxidative metabolism in the liver. However, according to the analysis of variance data, the inhibitory effect is dose dependent. At a dose of 1000 mg daily, ciprofloxacin may induce drug interactions whereas, at a dose of 250 mg daily, the likelihood of drug interactions is improbable. In study B, cimetidine (1000 mg orally daily) and ciprofloxacin (500 mg twice daily) were administered simultaneously to eight patients. Blood samples for the determination of ciprofloxacin concentrations were taken at 0, 1, 2, 4, 6, and 12 hr after dosing on the first and seventh day of drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Metabolic interactions of phencyclidine (PCP) and delta 9-tetrahydrocannabinol (THC) in the rat.
The in vitro effects of THC on the metabolism of PCP by rat liver were determined. Samples containing 1 mM PCP were incubated for 1 hr at 37 degrees C with an NADPH-generating system containing 10,000 X g supernatant or Ca++-precipitated rat liver microsomes. These incubations were carried out in the presence or absence of THC and at the end of 1 hr, PCP metabolites were determined by gas chromatography. In the presence of 0.1, 0.05, 0.025 and 0.0125 mM THC, the production of 1-(1-phenyl-4-hydroxycyclohexyl)piperidine (metabolite I) by the 10,000 X g supernatant was decreased by 46, 29, 23 and 16% respectively. Similarly, production of 1-(1-phenylcyclohexyl)-4-hydroxypiperidine (metabolite II) was reduced significantly by 58, 44, 34 and 23% with the respective concentrations of THC. However, the production of 1-phenylcyclohexylamine (metabolite III) was increased by 18, 32, 30 and 22% with 0.1, 0.05, 0.025 and 0.0125 mM THC. Incubations with Ca++-precipitated liver microsomes revealed similar trends in PCP metabolism in the presence or absence of THC. Metabolites I and II were reduced by 62 and 67% by 0.1 mM THC. Another concentration of THC (0.025 mM) caused a 50 and 62% decrease in I and II. These observations suggest that THC alters the in vitro microsomal metabolism of PCP.
Animals↗