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PubMed1998

Metabolic interactions between glucose and fatty acids in humans.

In vivo energy production results largely from the oxidative metabolism of either glucose or fatty acids. Under diverse physiologic and nutritional conditions, the oxidation of either glucose or fatty acids may predominate. The nature of the control of the availability and oxidation of each substrate has been studied extensively for > or = 30 y. The most popular and enduring hypothesis was proposed by Randle et al in 1963 and is termed the glucose-fatty acid cycle. This proposal places great significance on the regulation of lipolysis as a factor controlling substrate metabolism. Our work has led to an opposite perspective, which could be called the glucose-fatty acid cycle reversed. According to our hypothesis, the rate of glycolysis, determined by the intracellular availability of glucose-6-phosphate, is the predominant factor determining the rate of glucose oxidation. Whereas the rate of lipolysis may have some effect on the availability of glucose, both via a fatty acid-mediated inhibition of plasma glucose uptake and also by supplying glycerol for gluconeogenesis, there is little evidence for a direct inhibitory effect of fatty acid oxidation on the intracellular oxidation of glucose. In contrast, increased glucose oxidation limits oxidation of long-chain fatty acids directly by inhibiting their transport into the mitochondria. Consequently, whereas there is a close coupling between glucose availability and oxidation, fatty acids are generally available in greater quantities than are required for oxidation. We propose that fatty acid oxidation is largely controlled at the site of oxidation, which is in turn determined by the availability of glucose, rather than by its availability via lipolysis.

Dietary Carbohydrates↗
PubMed2004

Metabolic interaction between cyclosporine and sirolimus.

BACKGROUND: When the immunosuppressants cyclosporine (CsA) and sirolimus (SRL) are co-administered to transplant patients, lower doses are used than when either drug is given alone. Since both drugs share similar transport and metabolic pathways, there is the potential for an interaction leading to unpredictable effects. Furthermore, both drugs affect the activity of cytochrome P450 3A1/2 (CYP3A1/2), the rat parallel to human CYP3A4, and the multidrug transporter P-glycoprotein (Pgp). METHODS: To clarify the role of metabolic enzymes and membrane transporters involved in the disposition of both drugs, we examined hepatic CYP3A1/2, Pgp, and multidrug resistance gene (mdr) mRNA during chronic therapy with CsA and SRL in salt-depleted rats. Specifically, rats were given intravenous doses of CsA 2.5 mg/kg and SRL 1 mg/kg, alone or in combination, for two weeks via constant rate intravenous infusion. RESULTS: CsA treatment inhibited hepatic CYP3A1/2 protein expression, catalytic activity, and mRNA levels. SRL dosing suppressed CYP3A1/2 protein expression and catalytic activity, without affecting mRNA. With combined dosing, however, there was a much greater reduction. Hepatic Pgp protein levels were elevated after treatment with either drug alone, as well as with combined dosing. Compared to controls, there were significant increases in mdr1a and mdr1b mRNA levels in all treatment groups, with the combined drugs causing the greatest increase. CONCLUSIONS: Both CYP3A1/2 and Pgp participate in the disposition of CsA and SRL in rats. Changes in the individual activities of CYP3A1/2 and Pgp may contribute to an interaction between CsA and SRL resulting in unanticipated effects during chronic therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

Metabolic interaction between skeletal muscle and liver during bacteremia.

To study the effects of bacteremia on skeletal muscle leucine (LEU) metabolism, mongrel dogs were infused with normal saline or Escherichia coli (10(9)/kg). After a bolus dose (3.6 microCi), L(1-carbon 14) LEU (0.3 microCi/min) was infused directly into the isolated, constant-flow, in vivo gracilis muscle. Arteriovenous differences for amino acids, labeled and unlabeled LEU and alpha-ketoisocaproic acid (KIC), and labeled carbon dioxide were measured at ten-minute intervals for one hour. Bacteremia increased the net release of amino acids and total N2 from muscle. Moreover, plasma LEU that was deaminated and released as KIC was increased, and there was also an increase in decarboxylated plasma LEU during bacteremia. Despite the marked increase in KIC release from skeletal muscle during bacteremia, arterial concentrations were not significantly different from those of controls. An unchanged arterial plasma KIC concentration associated with a marked increase in KIC released from skeletal muscle indicates an increase in LEU metabolism, most likely in the liver. Thus, the increased skeletal muscle catabolism is not a futile cycle but rather an essential event to meet the increased metabolic needs of the body during bacteremia.

Amino Acids, Branched-Chain↗
PubMed1983

[Metabolic interactions of propyphenazone].

Pretreatment of female Wistar rats with propyphenazone produces a slight shortening of the hexobarbital sleeping time, and high doses of this drug cause a small increase in the relative liver weight, but there occurs no significant change in the N-demethylation of aminophenazone, the O-demethylation of codeine phosphate, the hydroxylation of aniline, the glucuronidation of p-nitrophenol, the cytochrome P-450 concentration and the NADPH-cytochrome c reductase activity in the 9.000 supernatant of liver homogenates. The differences between these properties of propyphenazone and those of aminophenazone and phenazone are discussed with reference to partition coefficients and biotransformation. The findings obtained do not justify the expectation of metabolic drug-drug interactions in case of repeated application of propyphenazone in the framework of a combined therapy.

Animals↗
PubMedDate not supplied

Metabolic interactions between glucose, glycerol, alanine and acetate in Leishmania braziliensis panamensis promastigotes.

13C-nuclear magnetic resonance (NMR) spectroscopy was used to investigate the products of glycerol and acetate metabolism released by Leishmania braziliensis panamensis promastigotes and also to examine the interaction of each of these substrates with glucose or alanine. The NMR data were supplemented by measurements of the rates of oxygen consumption and substrate utilization, and of 14CO2 production from 14C-labeled substrate. Cells incubated with [2-13C]glycerol released acetate, succinate and D-lactate in addition to CO2. Cells incubated with acetate released only CO2. More succinate C-2/C-3 than C-1/C-4 was released from both [2-13C]glycerol and [2-13C]glucose, indicating that succinate was formed predominantly by CO2 fixation followed by reverse flux through part of the Krebs cycle. Some redistribution of the position of labeling was also seen in alanine and pyruvate, suggesting cycling through pyruvate/oxaloacetate/phosphoenolpyruvate. Cells incubated with combinations of 2 substrates consumed oxygen at the same rate as cells incubated with 1 or no substrate, even though the total substrate utilization had increased. When promastigotes were incubated with both glycerol and glucose, the rate of glucose consumption was unchanged but glycerol consumption decreased about 50%, and the rate of 14CO2 production from [1,(3)-14C]glycerol decreased about 60%. Alanine did not affect the rates of consumption of glucose or glycerol, but decreased 14CO2 production from these substrates by increasing flow of label into alanine. Although glucose decreased alanine consumption by 70%, it increased the rate of 14CO2 production from [U-14C]- and [l-14C]alanine by about 20%.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMedDate not supplied

Pattern of cerebral metabolic interactions in a subject with isolated amnesia at risk for Alzheimer's disease: a longitudinal evaluation.

A pattern of reduced cerebral metabolic rate for glucose (rCMRglc) has been shown by positron emission tomography (PET) in patients with dementia of the Alzheimer type. To verify if a similar rCMRglc pattern is present in subjects 'at risk' for Alzheimer's disease (AD), we used high-resolution PET to longitudinally study a subject with isolated memory impairment and a family history for autosomal dominant AD. Initial rCMRglc data did not reveal any consistent abnormality as compared to a group of sex- and age-matched healthy controls. However, 1 year later, a follow-up evaluation did reveal reduced parietal rCMRglc values coinciding with a worsening of cognitive impairment, which suggested that standard analyses of resting rCMRglc data may not be useful in the early diagnosis of AD. In contrast, when a previously determined discriminant function for distinguishing controls from AD patients was applied, the subject was correctly identified as an AD patient on both PET scans.

Aged↗
PubMedDate not supplied

[A case of metabolic interaction: amitriptyline, fluoxetine, antitubercular agents].

Polytherapy is often used in clinical practice. The drug associations may lead to pharmacokinetic and/or pharmacodynamic interactions, with clinical implications. The authors reported a quantified illustration of 2 types of interactions in a depressed patient: between antidepressants, amitriptyline and fluoxetine, between these antidepressants and antituberculosis. Firstly, when fluoxetine was added to amitriptyline, it was observed, as expected, an increase of the tricyclic and its metabolite plasma levels, despite a decrease of its dosage. Secondly, when antituberculosis were added to the 2 antidepressants, it was observed a decrease of the tricyclic drug plasma levels. These levels remained below the therapeutic window even when the tricyclic antidepressant dosage was increased. It seems that the fluoxetine interaction disappeared. The competition between the inhibitory effect of fluoxetine and the induction of rifampicin, on the metabolism of amitriptyline is discussed.

Adult↗
PubMed2003

The pentylenetetrazole-kindling model of epilepsy in SAMP8 mice: glial-neuronal metabolic interactions.

Recently, a new experimental model of epilepsy was introduced by the authors [Neurochem. Int. 40 (2002) 413]. This model combines pentylenetetrazole (PTZ)-kindling in senescence-accelerated mice P8 (SAMP8), a genetic model of aging. Since imbalance of glutamate and GABA is a major cause of seizures, the study of glial-neuronal interactions is of primary importance. Nuclear magnetic resonance spectroscopy (NMRS) is an excellent tool for metabolic studies. Thus, we examined whether NMRS when combined with administration of [1-13C]glucose and [1,2-13C]acetate might give valuable insights into neurotransmitter metabolism in this new model of epilepsy and aging. The 2- and 8-month-old SAMP8 were kindled with PTZ alone, received PTZ and phenobarbital (PB), or served as controls. In older animals, PTZ-kindling decreased labeling in glutamate C-4 from [1-13C]glucose, whereas, in the younger mice, labeling in glutamine C-4 was decreased both from [1-13C]glucose and [1,2-13C]acetate. It could be concluded that PTZ-kindling affected astrocytes in younger and glutamatergic neurons in older animals. In the presence of PTZ, phenobarbital decreased labeling of most metabolites in all cell types, except GABAergic neurons, from both labeled precursors in the younger animals. However, in older animals only GABAergic neurons were affected by phenobarbital as indicated by an increase in GABA labeling.

Acetic Acid↗
PubMed2002

[Metabolic interaction between psychopharmaceuticals. Probable cause of exacerbation of hypothyroidism according to a case report].

Little is known about how psychotropic drugs influence thyroid function in man, but it has been reported that sertraline decreases the efficacy of levothyroxine in patients treated for hypothyroidism. Most psychotropic drugs are metabolized in the liver by cytochrome P450. Sertraline is metabolized by cytochrome P450 CYP 2D6, CYP 3A4, and CYP 2C19. Mianserin is metabolized by CYP 2D6, and to some extent also by CYP 3A4. Since both substances, at least in part, are metabolized by the same liver enzymes, drug interactions can be expected. In this article we describe such a possible interaction between sertraline and mianserin in a patient treated with levothyroxine for hypothyroidism (Hashimoto's thyroiditis). She displayed both clinical symptoms and laboratory data typical of hypothyroidism when long-term antidepressive sertraline therapy (100 mg/day) was transiently supplemented with mianserin (30 mg/day). All symptoms and signs of hypothyroidism disappeared completely when the mianserin treatment was discontinued. These findings imply that unexpected drug effects may occur in depressed patients with primary hypothyroidism if they are treated with both sertraline and mianserin. In such situations thyroid function should be checked carefully.

Antidepressive Agents↗
PubMed1987

Quantitative evaluation of the metabolic interactions between trichloroethylene and 1,1-dichloroethylene in vivo using gas uptake methods.

Gas uptake simulation methods were used to determine kinetic constants for trichloroethylene (TCE) and 1,1-dichloroethylene (1,1-DCE) metabolism in vivo in male Fischer 344 rats. Both are metabolized by single, saturable, oxidative pathways with high-affinity substrate binding. The allometrically scaled maximum velocities (Vmaxc) for TCE and 1,1-DCE were, respectively, 11 and 7.5 mg/hr (i.e., 84 and 77 mumol/hr). Gas uptake studies were also conducted with three mixed atmosphere exposures with the following initial concentrations in parts per million: 500 (1,1-DCE):2000 (TCE); 500 (1,1-DCE):500 (TCE); and 2000 (1,1-DCE):500 (TCE). Mixture uptake curves were described by a system of equations in which a full physiologically based pharmacokinetic (PB-PK) model was provided for each chemical and each was regarded as an inhibitor of the other's metabolism. A generic model was developed to accommodate multiple mechanisms of inhibitory interactions, i.e., competitive, noncompetitive, or uncompetitive. An excellent correspondence was obtained between predicted and observed behavior when the inhibition was assumed to be purely competitive with binding constants for TCE and 1,1-DCE set to 0.25 and 0.10 mg/liter, respectively; i.e., in vivo 1,1-DCE is a slightly better substrate for microsomal oxidation than is TCE. The PB-PK model which was successful in describing the mixture data was used to predict conditions under which 1,1-DCE hepatotoxicity would be expected in coexposure to constant concentration atmospheres of these two chloroethylenes. These predictions were compared with data on the increases in plasma liver enzymes resulting from exposures to either 1,1-DCE alone or to 1,1-DCE in combination with TCE.

Animals↗
PubMed1980

[Mathematical model of carbohydrate energy metabolism. Interaction between glycolysis, the Krebs cycle and the H-transporting shuttles at varying ATPase load].

A simple mathematical model for carbohydrate energy metabolism based on the stoichiometic structure of glycolysis, the Krebs cycle and oxidative phosphorylation is proposed. The only allosteric regulation involved in the model is phosphofructokinase activation by AMP. Simple as it is, the model can explain the following properties of carbohydrate metabolism: a drastic rise of the rate of glucose consumption during transition to a higher level of ATPase load; stabilization of ATP and an increase of the steady state rates of glycolysis and oxidation of cytoplasmic NADH by the H-transporting shuttles and of pyruvate in the Krebs cycle with increasing rate of the ATPase load; activation of glycolysis and a decrease of the rate of oxidative phosphorylation following an inhibition of the H-transporting shuttles. The mechanisms of the coordinated changes in the steady state rates of glycolysis, the H-transporting shuttles and the Krebs cycle at varying ATPase load in the cell are discussed.

Adenosine Triphosphatases↗
PubMed1980

Phenytoin-misonidazole: possible metabolic interaction.

Following iv administration of misonidazole, evidence of decreased plasma half-life (3.8 hours versus 9.1 hours +/- 0.8 [SD] in eight other patients studied) and increased metabolism was observed in a patient receiving continuous phenytoin therapy.

Drug Evaluation↗
PubMed1992

[The metabolic interaction of cobalt and silver in the body during their combined action].

Mixtures of cobalt and silver in ratio (0.2:0.4), (0.2:0.2) and (0.2:0.1) mg/kg were once administrated intraperitoneally and intratracheally to white rats. Metabolism of the metals was studied. Combined exposure to metals appeared to influence greatly on their toxicokinetics. The co-action between metals appears during their absorption into the blood--the elevated peritoneal absorption of cobalt depresses that of silver. The reverse relationship is demonstrated during the intratracheal insertion. Such peculiarities of co-action exist during the further stages of metabolism.

Absorption↗
PubMed2006

The effects of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene on glucose/insulin metabolism interact with prenatal exposure to famine.

OBJECTIVE: An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism. RESEARCH DESIGN AND METHODS: We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-gamma2 genotype among 675 term singletons born around the time of the 1944-1945 Dutch famine. RESULTS: A significant interaction effect between exposure to famine during midgestation and the PPAR-gamma2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-gamma2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation. CONCLUSIONS: The effects of the PPAR-gamma2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic beta-cell maldevelopment and carrier type of the Ala allele in the PPAR-gamma2 gene.

Aged↗
PubMed1996

Metabolic interactions between essential and trans-fatty acids.

Trans-fatty acids exacerbate essential fatty acid deficiency in experimental animals by interfering with the metabolism of linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acids and, hence, the eicosanoid production. The interfering effect depends on the type of trans-fatty acid. The detrimental effect of trans-fatty acid, however, apparently disappears when dietary linoleic acid is sufficiently supplemented. Trans-fatty acids appear to disturb fetal growth and birth weight, possibly by the same mechanism.

Animals↗
PubMed1984

The stimulus-secretion coupling of amino acid-induced insulin release metabolic interaction of L-asparagine and L-leucine in pancreatic islets.

Because L-asparagine augments insulin release evoked by L-leucine, the metabolism of these two amino acids was investigated in rat pancreatic islets. L-Leucine inhibited the uptake and deamidation of L-asparagine, but failed to exert any obvious primary effect upon the further catabolism of aspartate derived from exogenous asparagine. L-Asparagine augmented the oxidation of L-leucine, an effect possibly attributable to activation of 2-ketoisocaproate dehydrogenase. The association of L-asparagine and L-leucine exerted a sparing action on the utilization of endogenous amino acids, so that the integrated rate of nutrients oxidation was virtually identical in the sole presence of L-leucine and simultaneous presence of L-asparagine and L-leucine, respectively. It is proposed that the enhancing action of L-asparagine upon insulin release evoked by L-leucine is attributable to an increased generation rate of cytosolic NADPH rather than any increase in nutrients oxidation.

Animals↗
PubMed2006

Possible drug-metabolism interactions of medicinal herbs with antiretroviral agents.

Herbal medicines are widely used by HIV patients. Several herbal medicines have been shown to interact with antiretroviral drugs, which might lead to drug failure. We have aimed to provide an overview of the modulating effects of Western and African herbal medicines on antiretroviral drug-metabolizing and transporting enzymes, focusing on potential herb-antiretroviral drug interactions. Echinacea, garlic, ginkgo, milk thistle, and St. John's wort have the potential to cause significant interactions. In vitro and in vivo animal studies also indicated other herbs with a potential for interactions; however, most evidence is based on in vitro studies. Further pharmacokinetic studies to unveil potential Western and especially African herb-antiretroviral drug interactions are urgently required, and the clinical significance of these interactions should be assessed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗