Metabolic Interactions (metabolic + interaction)

Distribution by Scientific Domains


Selected Abstracts


A comparison of drug overdose deaths involving methadone and other opioid analgesics in West Virginia

ADDICTION, Issue 9 2009
Leonard J. Paulozzi
ABSTRACT Aims To describe all people dying from unintentional overdoses of methadone or other opioid analgesics (OOA) in West Virginia in 2006. Design We analyzed medical examiner data supplemented by data from the state prescription drug monitoring program. We compared people whose deaths involved methadone with those whose deaths involved OOA. Findings The methadone group included 87 decedents, and the OOA group included 163 decedents. Most were male. Decedents in the methadone group were significantly younger than those in the OOA group: more than a quarter were 18,24 years of age. For both groups, approximately 50% had a history of pain, and 80% had a history of substance abuse. There was no intergroup difference in the prevalence of benzodiazepines at post-mortem. Methadone was significantly less likely to have ever been prescribed than OOA. Among those with prescriptions, the proportion prescribed within 30 days of death was significantly greater for methadone than for hydrocodone, but not for oxycodone. Ten (11.5%) of the methadone decedents were enrolled in an opiate treatment program (OTP) at the time of death. Conclusions The high prevalence of a substance abuse history and lack of prescriptions suggest that most of the deaths in both groups are related to substance abuse. There was no indication of a harmful effect from methadone's metabolic interaction with benzodiazepines, but provider or patient unfamiliarity with methadone may have been a risk factor. Prescribing methadone, especially to young males, requires extra care. Providers, OTPs and coroners/medical examiners should use state prescription drug monitoring programs to monitor the use of controlled substances by their patients. [source]


Prediction of herb,drug metabolic interactions: a simulation study

PHYTOTHERAPY RESEARCH, Issue 6 2005
Shufeng Zhou
Abstract In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb,drug interactions. An attempt was made to simulate the effects of herbal preparation with single or multiple CYP-inhibiting constituents on the area of the plasma concentration-time curve (AUC) of coadministered drug that was either a low clearance drug by intravenous (i.v.) injection or a high clearance drug by oral route. Our simulation studies indicated that the expected increase (Rc) in the AUC of the coadministered drug by inhibiting herbal constituent(s) was dependent on the route of administration. For low clearance drug by i.v. injection, Rc was generally determined by inhibition constant (Ki), unbound inhibitor concentration ([I]), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm), while Rc for a high clearance drug by oral route, Rc was determined by Ki, [I], n and fm. By varying these parameters, Rc changed accordingly. It appeared likely to predict a herb,drug metabolic interaction, if the inhibiting herbal constituents could be quantitatively determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and thus in vivo animal and human studies are always necessary. Copyright © 2005 John Wiley & Sons, Ltd. [source]


Metabolic profiling as a tool for revealing Saccharomyces interactions during wine fermentation

FEMS YEAST RESEARCH, Issue 1 2006
Kate S. Howell
Abstract The multi-yeast strain composition of wine fermentations has been well established. However, the effect of multiple strains of Saccharomyces spp. on wine flavour is unknown. Here, we demonstrate that multiple strains of Saccharomyces grown together in grape juice can affect the profile of aroma compounds that accumulate during fermentation. A metabolic footprint of each yeast in monoculture, mixed cultures or blended wines was derived by gas chromatography , mass spectrometry measurement of volatiles accumulated during fermentation. The resultant ion spectrograms were transformed and compared by principal-component analysis. The principal-component analysis showed that the profiles of compounds present in wines made by mixed-culture fermentation were different from those where yeasts were grown in monoculture fermentation, and these differences could not be produced by blending wines. Blending of monoculture wines to mimic the population composition of mixed-culture wines showed that yeast metabolic interactions could account for these differences. Additionally, the yeast strain contribution of volatiles to a mixed fermentation cannot be predicted by the population of that yeast. This study provides a novel way to measure the population status of wine fermentations by metabolic footprinting. [source]


Metabolic drug interactions with new psychotropic agents

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2003
Edoardo Spina
Abstract New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and ,third generation' antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s). [source]


Inhibition of fipronil and nonane metabolism in human liver microsomes and human cytochrome P450 isoforms by chlorpyrifos

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2007
Hyun Joo
Abstract Previous studies have established that chlorpyrifos (CPS), fipronil, and nonane can all be metabolized by human liver microsomes (HLM) and a number of cytochrome P450 (CYP) isoforms. However, metabolic interactions between these three substrates have not been described. In this study the effect of either coincubation or preincubation of CPS with HLM or CYP isoforms with either fipronil or nonane as substrate was investigated. In both co- and preincubation experiments, CPS significantly inhibited the metabolism of fipronil or nonane by HLM although CPS inhibited the metabolism of fipronil more effectively than that of nonane. CPS significantly inhibited the metabolism of fipronil by CYP3A4 as well as the metabolism of nonane by CYP2B6. In both cases, preincubation with CPS caused greater inhibition than coincubation, suggesting that the inhibition is mechanism based. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:76,80, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20161 [source]


Extrapolating in vitro metabolic interactions to isolated perfused liver: Predictions of metabolic interactions between R -bufuralol, bunitrolol, and debrisoquine

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2010
Sami Haddad
Abstract Drug,drug interactions (DDIs) are a great concern to the selection of new drug candidates. While in vitro screening assays for DDI are a routine procedure in preclinical research, their interpretation and relevance for the in vivo situation still represent a major challenge. The objective of the present study was to develop a novel mechanistic modeling approach to quantitatively predict DDI solely based upon in vitro data. The overall strategy consisted of developing a model of the liver with physiological details on three subcompartments: the sinusoidal space, the space of Disse, and the cellular matrix. The substrate and inhibitor concentrations available to the metabolizing enzyme were modeled with respect to time and were used to relate the in vitro inhibition constant (Ki) to the in vivo situation. The development of the liver model was supported by experimental studies in a stepwise fashion: (i) characterizing the interactions between the three selected drugs (R -bufuralol (BUF), bunitrolol (BUN), and debrisoquine (DBQ)) in microsomal incubations, (ii) modeling DDI based on binary mixtures model for all the possible pairs of interactions (BUF,BUN, BUF,DBQ, BUN,DBQ) describing a mutual competitive inhibition between the compounds, (iii) incorporating in the binary mixtures model the related constants determined in vitro for the inhibition, metabolism, transport, and partition coefficients of each compound, and (iv) validating the overall liver model for the prediction of the perfusate kinetics of each drug determined in isolated perfused rat liver (IPRL) for the single and paired compounds. Results from microsomal coincubations showed that competitive inhibition was the mechanism of interactions between all three compounds, as expected since those compounds are all substrates of rat CYP2D2. For each drug, the Ki values estimated were similar to their Km values for CYP2D2 indicative of a competition for the same substrate-binding site. Comparison of the performance between the novel liver physiologically based pharmacokinetic (PBPK) model and published empirical models in simulating the perfusate concentration,time profile was based on the area under the curve (AUC) and the shape of the curve of the perfusate time course. The present liver PBPK model was able to quantitatively predict the metabolic interactions determined during the perfusions of mixtures of BUF,DBQ and BUN,DBQ. However, a lower degree of accuracy was obtained for the mixtures of BUF,BUN, potentially due to some interindividual variability in the relative proportion of CYP2D1 and CYP2D2 isoenzymes, both involved in BUF metabolism. Overall, in this metabolic interaction prediction exercise, the PBPK model clearly showed to be the best predictor of perfusate kinetics compared to more empirical models. The present study demonstrated the potential of the mechanistic liver model to enable predictions of metabolic DDI under in vivo condition solely from in vitro information. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4406,4426, 2010 [source]


Role of proton MR for the study of muscle lipid metabolism,

NMR IN BIOMEDICINE, Issue 7 2006
Chris Boesch
Abstract 1H-MR spectroscopy (MRS) of intramyocellular lipids (IMCL) became particularly important when it was recognized that IMCL levels are related to insulin sensitivity. While this relation is rather complex and depends on the training status of the subjects, various other influences such as exercise and diet also influence IMCL concentrations. This may open insight into many metabolic interactions; however, it also requires careful planning of studies in order to control all these confounding influences. This review summarizes various historical, methodological, and practical aspects of 1H-MR spectroscopy (MRS) of muscular lipids. That includes a differentiation of bulk magnetic susceptibility effects and residual dipolar coupling that can both be observed in MRS of skeletal muscle, yet affecting different metabolites in a specific way. Fitting of the intra- (IMCL) and extramyocellular (EMCL) signals with complex line shapes and the transformation into absolute concentrations is discussed. Since the determination of IMCL in muscle groups with oblique fiber orientation or in obese subjects is still difficult, potential improvement with high-resolution spectroscopic imaging or at higher field strength is considered. Fat selective imaging is presented as a possible alternative to MRS and the potential of multinuclear MRS is discussed. 1H-MRS of muscle lipids allows non-invasive and repeated studies of muscle metabolism that lead to highly relevant findings in clinics and patho-physiology. Copyright © 2006 John Wiley & Sons, Ltd. [source]


Prediction of herb,drug metabolic interactions: a simulation study

PHYTOTHERAPY RESEARCH, Issue 6 2005
Shufeng Zhou
Abstract In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb,drug interactions. An attempt was made to simulate the effects of herbal preparation with single or multiple CYP-inhibiting constituents on the area of the plasma concentration-time curve (AUC) of coadministered drug that was either a low clearance drug by intravenous (i.v.) injection or a high clearance drug by oral route. Our simulation studies indicated that the expected increase (Rc) in the AUC of the coadministered drug by inhibiting herbal constituent(s) was dependent on the route of administration. For low clearance drug by i.v. injection, Rc was generally determined by inhibition constant (Ki), unbound inhibitor concentration ([I]), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm), while Rc for a high clearance drug by oral route, Rc was determined by Ki, [I], n and fm. By varying these parameters, Rc changed accordingly. It appeared likely to predict a herb,drug metabolic interaction, if the inhibiting herbal constituents could be quantitatively determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and thus in vivo animal and human studies are always necessary. Copyright © 2005 John Wiley & Sons, Ltd. [source]


Inhibitory Effects of Silibinin on Cytochrome P-450 Enzymes in Human Liver Microsomes

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2000
Svane Beckmann-Knopp
Silibinin, the main constituent of silymarin, a flavonoid drug from silybum marianum used in liver disease, was tested for inhibition of human cytochrome P-450 enzymes. Metabolic activities were determined in liver microsomes from two donors using selective substrates. With each substrate, incubations were carried out with and without silibinin (concentrations 3.7,300 ,M) at 37° in 0.1 M KH2PO4 buffer containing up to 3% DMSO. Metabolite concentrations were determined by HPLC or direct spectroscopy. First, silibinin IC50 values were determined for each substrate at respective KM concentrations. Silibinin had little effect (IC50>200 ,M) on the metabolism of erythromycin (CYP3A4), chlorzoxazone (CYP2E1), S(+)-mephenytoin (CYP2C19), caffeine (CYP1A2) or coumarin (CYP2A6). A moderate effect was observed for high affinity dextromethorphan metabolism (CYP2D6) in one of the microsomes samples tested only (IC50=173 ,M). Clear inhibition was found for denitronifedipine oxidation (CYP3A4; IC50=29 ,M and 46 ,M) and S(,)-warfarin 7-hydroxylation (CYP2C9; IC50=43 ,M and 45 ,M). When additional substrate concentrations were tested to assess enzyme kinetics, silibinin was a potent competitive inhibitor of dextromethorphan metabolism at the low affinity site, which is not CYP2D6 (Ki,c=2.3 ,M and 2.4 ,M). Inhibition was competitive for S(,)-warfarin 7-hydroxylation (Ki,c=18 ,M and 19 ,M) and mainly non-competitive for denitronifedipine oxidation (Ki,n=9 ,M and 12 ,M). With therapeutic silibinin peak plasma concentrations of 0.6 ,M and biliary concentrations up to 200 ,M, metabolic interactions with xenobiotics metabolised by CYP3A4 or CYP2C9 cannot be excluded. [source]


Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2004
Michael Hall
Abstract Dexloxiglumide (DEX) is a cholecystokinin type-1 receptor antagonist under development for the treatment of constipation-predominant irritable bowel syndrome. Studies of the potential interaction of DEX with human cytochromes P450 (CYPs) were conducted in vitro. DEX (300µM), both with and without a 15-min pre-incubation, was incubated with pooled human liver microsomes and substrates selective for each of eight CYPs. This resulted in >30% inhibition of tolbutamide 4-methyl-hydroxylase (CYP2C9/10) and lauric acid 11-hydroxylase (CYP2E1) activities. Mean Ki (SD) for CYP2C9/10 and CYP2E1 were 69.0 (24.3) and 426 (60)µM, respectively. Incubations of [14C]DEX with pooled human liver microsomes produced one major phase I metabolic fraction, with Vmax=131 pmol/min/mg protein and Km=23.7µM. Further incubations with (i) liver microsomes from 16 individual donors (correlation analysis), (ii) SupersomesÔ and (iii) selective chemical inhibitors, implicated CYP3A4/5, CYP2B6 and CYP2C9 in the formation of this component. Thus, DEX interacts with CYP2C9 both as inhibitor (Ki=69.0µM) and as substrate in vitro. However, based on the maximum concentration (27µM) after repeated oral doses of 200mg t.i.d. and the unbound fraction (0.03) of DEX in human plasma, no clinically relevant metabolic interactions with other CYP substrates are predicted. Copyright © 2004 John Wiley & Sons, Ltd. [source]