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Biomedical subjects

R T Coutts

Publications and source records attributed to R T Coutts.

At least 37 records · Page 2Linked to original sources
PubMed1997

Adverse drug reactions and debrisoquine/sparteine (P450IID6) polymorphism in patients with fibromyalgia.

OBJECTIVE: To assess the frequency of adverse drug reaction in patients with fibromyalgia in relation to medications prescribed for this condition. To evaluate the potential role of the P450IID6 phenotype in the pathogenesis of these adverse drug reactions. METHODS: Thirty-five patients with fibromyalgia were assessed using a structured questionnaire with demographic and clinical data and perceived adverse drug reactions. A sample of 60 patients with rheumatoid arthritis and 62 patients with localized back pain served as controls. The P450IID6 phenotype was determined for each of the fibromyalgia patients. RESULTS: Overall, 141 patients had used NSAID and 79 (56%) of them reported adverse effects. Antidepressant drugs were used by 68 patients and 35 (51%) patients had adverse effects. Muscle relaxant drugs were used by 48 patients and 15 (31%) of them reported side effects. Analgesics were used by 122 patients and 22 (18%) had experienced adverse effects. Statistical differences in the frequency of adverse effects were found with antidepressant drugs in the fibromyalgia group, compared with rheumatoid arthritis (p=0.01) and back pain (p=0.02). Four of the 35 patients (11.4%) had a metabolic ratio (M.R.) greater than 0.30 (log M.R.= -0.52) indicative of the poor metabolizers (PM) phenotype. M.R. varied from 0.005 (log M.R. = -2.30) to 4.99 (log M.R. = 0.70). CONCLUSIONS: The problem of adverse drug reactions in fibromyalgia patients does not appear to correlate with the PM phenotype of the P450IID6 oxidative enzyme. It also is unlikely that altered xenobiotic detoxification attributable to this PM phenotype would have a significant role in the development of fibromyalgia.

Adult↗
PubMed1997

A rapid and sensitive electron-capture gas chromatographic procedure for analysis of metoprolol in rat brain and heart.

A procedure for analysis of metoprolol-utilizing extraction followed by derivatization with pentafluoropropionic anhydride and analysis on a gas chromatograph equipped with a fused silica capillary column, an electron-capture detector and a printer/integrator is described. Propranolol was carried through the procedure as internal standard. The pentafluoropropionyl derivative of metoprolol yields a sharp peak on the gas chromatograph, and the structure of the derivative was confirmed using combined gas chromatography-mass spectrometry. The analytical method is linear, sensitive and reproducible and has been applied to analysis of metoprolol in brain and heart from rats treated with metoprolol intraperitoneally. Pretreatment of the rats with the antidepressant desipramine prior to metoprolol administration resulted in a marked increase in levels of metoprolol in both brain and heart, indicating a pharmacokinetic drug-drug interaction between desipramine and metoprolol.

Animals↗
PubMed1997

Effects of intravenous infusion of lidocaine on its pharmacokinetics in conscious instrumented dogs.

In this study, potential alterations in hepatic blood flow, plasma protein binding, hepatic tissue binding, and enzyme activities induced by LD iv infusion of lidocaine (LD) were evaluated using a chronically instrumented dog model. Four conscious female mongrel dogs (19.0-23.5 kg) were each given, on days 1 and 10, a 5-min infusion of a mixture of unlabeled LD at approximately 2 mg/kg and 14C-labeled LD at approximately 25 microCi and, on day 8, a 12-h constant rate iv infusion of LD (approximately 76 microg/kg/min). During LD infusion, there was a 11-79% increase in total hepatic blood flow, mainly due to a 1.6-9.2-fold increase in hepatic arterial flow. Despite similar blood clearance (27.5 +/- 6.0 mL/min/kg vs 27.5 +/- 3.5 mL/min/kg), volume of distribution at steady state (1.38 +/- 0.08 L/kg vs 1.36 +/- 0.17 L/kg), and free fraction values of LD between days 1 and 10 (p > 0.05), intrinsic clearance values were consistently reduced (1224 +/- 859 mL/ min/kg vs 285 +/- 104 mL/min/kg; p = 0.034). Furthermore, hepatic tissue uptake of LD and/or its metabolites was less on day 10 than on day 1 (39.7 +/- 14.5 micromol vs 30.1 +/- 15.1 micromol; p = 0.072). The extent of N-dealkylation of LD to MEGX was unaltered, whereas sequential biotransformation of MEGX was impaired. Hence, these findings suggested that LD infusion led to a reduction of hepatic intrinsic clearance, although the change was not significant enough to alter its conventional kinetic parameters.

Animals↗
PubMed1997

Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol.

1. Human cytochrome P450 (CYP) isoenzymes expressed in a human cell line were used to elucidate their involvement in the metabolism of haloperidol (HAL). 2. It was found that CYP3A4 catalyzes the metabolism of HAL to HAL 1,2,3,6-tetrahydropyridine (HTP). HTP is further metabolized to HAL pyridinium (HP+) by both CYP3A4 and CYP2D6. 3. CYP3A4 and CYP2D6 are also responsible for the N-dealkylation of HAL. The N-dealkylation of reduced HAL (RH) was observed, which is catalyzed by CYP3A4. In addition, CYP3A4 also catalyzes the oxidation of RH back to HAL. 4. These results are discussed in terms of the metabolic interactions of HAL with other drugs and how this knowledge may be used to reduce the movement disorders induced by HAL.

Biotransformation↗
PubMed1997

Metabolism of amitriptyline with CYP2D6 expressed in a human cell line.

1. Expressed human cytochrome P450 enzyme CPY2D6 was used to metabolize amitriptyline (AMI). It was established that CYP2D6 not only catalyzed ring 10-hydroxylation of AMI, but also mediated its N-demethylation to nortriptyline (NT), as well as the formation of 10-hydroxy-NT from NT. When the metabolism of AMI by CYP2D6 was repeated in the presence of quinidine, none of the metabolites, 10-hydroxy-AMI, NT and 10-hydroxy-NT, was formed. 2. Biochemical parameters of NT formation from AMI were determined, yielding Km = 47.48 +/- 1.32 microM; Vmax = 3.95 +/- 0.11 nmol/h/mg protein. The same parameters were calculated for the formation of 10-hydroxy-AMI (E + Z-isomers) from AMI, yielding Km = 10.70 +/- 0.20 microM; Vmax = 8.99 +/- 0.47 nmol/h/mg protein. 3. The formation of 10-hydroxy-NT from AMI proceeded primarily via NT and to a much lesser extent via 10-hydroxy-AMI. 4. Quantitative analyses of AMI and its metabolites were difficult to reproduce when the metabolites were analysed underivatized. Two derivatization procedures, acetylation and trifluoroacetylation, were employed to improve assay reproducibility.

Acylation↗
PubMed1997

Stereoselective metabolism of rac-mexiletine by the fungus Cunninghamella echinulata yields the major human metabolites hydroxymethylmexiletine and p-hydroxymexiletine.

rac-Mexiletine is an orally effective class 1b antiarrhythmic agent used to treat ventricular arrhythmias. In vivo experiments have demonstrated. It is predominantly metabolized by the liver with < 10% excreted as unchanged drug. The major mammalian metabolites have been identified as p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM). The purpose of our study was to determine whether the fungus Cunninghamella echinulata, which possesses a cytochrome P450 system analogous to that found in humans, could be used as a suitable in vitro model for studying the oxidative metabolism of rac-mexiletine. To accomplish this, a high performance liquid chromatographic assay was used that was capable of simultaneously quantifying the enantiomers of mexiletine, HMM, and PHM. Utilizing this procedure, it was demonstrated that C. echinulata stereoselectively converted rac-mexiletine into HMM (4% of added drug) and PHM (32% of added drug) after an incubation period of 50 hr. In addition, metabolite biosynthesis could be optimized by altering fermentation media components. Seven media values and seven pH values were evaluated. It was determined that a medium at pH 7.0 containing yeast extract and sucrose yielded optimal amounts of metabolites.

Anti-Arrhythmia Agents↗
PubMed1996

Determination of 4-(4-chlorophenyl)-4-hydroxypiperidine, a metabolite of haloperidol, by gas chromatography with electron-capture detection.

An electron-capture gas chromatographic procedure was developed for the analysis of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a metabolite of haloperidol. The assay involved basic extraction of this metabolite from the biological samples, followed by back-extraction with HCl. After basification of the acid phase, extractive derivatization with pentafluorobenzoyl chloride in toluene was conducted. The pentafluorobenzoyl derivative was quantified on a gas chromatograph equipped with a fused-silica capillary column, an electron-capture detector and a printer-integrator. N-(3-Trifluoromethylphenyl)piperazine was carried through the procedure as an internal standard and calibration curves were determined for each assay run. The procedure was demonstrated to be linear and reproducible and was utilized to detect and quantify CPHP in urine, plasma, brain and liver samples from rats treated with haloperidol. The structure of the derivatized metabolite was confirmed by gas chromatography-mass spectrometry.

Animals↗
PubMed1996

The antidepressant drug phenelzine produces antianxiety effects in the plus-maze and increases in rat brain GABA.

Research on the effects of antidepressant/ antipanic drugs in animal models of anxiety has yielded equivocal results, even after chronic drug regimens. In contrast, we found that the antidepressant/antipanic drug phenelzine, given acutely, produced a clear anxiolytic effect in the elevated plus-maze, a widely-used animal model of "anxiety" that is primarily sensitive to benzodiazepine-type anxiolytics (e.g., diazepam). Furthermore, the effective dose of phenelzine (15 mg/kg) administered to rats was associated with more than a 2- fold increase in whole brain levels of gamma-aminobutyric acid (GABA), whereas an ineffective dose of phenelzine (5.1 mg/kg) did not significantly change GABA levels. The N-acetylated metabolite of phenelzine, N2-acetylphenelzine, produced neither an anxiolytic effect in the elevated plus-maze nor a significant change in whole-brain levels of GABA. However, both phenelzine and N2-acetylphenelzine potently inhibited monoamine oxidase, a mechanism commonly thought to be involved in the therapeutic effects of monoamine oxidase inhibitors such as phenelzine in the treatment of depression in humans. These results suggest that the mechanism whereby phenelzine produces anxiolytic effects in the plus-maze model is unique to a facilitatory action on brain levels of GABA, in contrast to classical benzodiazepines, which produce anxiolytic effects by enhancing the affinity of the GABAA-receptor for GABA.

Animals↗
PubMed1996

Effects of light-exposed parenteral nutrition on hepatic function and lidocaine metabolism: a study using isolated rat liver perfusion.

Effects of light-exposed parenteral solutions on hepatic function and lidocaine metabolism were studied. Male rats (190-220 g) were randomly assigned to one of the three isocaloric treatment groups: parenteral nutrition (PN) (+L) group (n = 6), animals received a solution of 24.2% dextrose and 5.2% amino acids with light exposure; PN(-L) group (n = 5), animals received the same solution without light exposure; and CF group, chow-fed animals (n = 6) that received rat chow and water. Average energy intake in these animals was approximately 33 kcal/100 g/d. Lidocaine metabolism was studied in livers isolated from animals 7 d after treatment. Liver morphology indicated that five livers from PN(+L) animals developed steatosis. The lidocaine metabolism rate was the slowest in PN(+L) animals; this is marked by changes in the steady state levels (% dose) of lidocaine [PN(+L), 47.9 +/- 17.6; PN(-L), 25.9 +/- 2.1; versus CF, 11.3 +/- 5.3; p < 0.05]. The extraction ratio and intrinsic clearance values were reduced by 41 and 86% in PN(+L) group and 16 and 70% in PN(-L) group, respectively, when compared with CF (p < 0.05). Metabolite to drug ratios indicated that N-dealkylation, ring-hydroxylation, and aryl methyl hydroxylation of lidocaine were severely impaired, particularly in the PN(+L) animals. The extents of reduction in metabolic pathways were in the ranges 79-95% in the PN(+L) group and 44-90% in the PN(-L) (p < 0.05). These findings suggest that parenteral nutrition infusion induces steatosis and reduces the rate of lidocaine metabolism and exposure of parenteral nutrition solutions to light exacerbates this change.

Amino Acids↗
PubMed1996

Effects of taurine supplementation in parenteral nutrition-associated hepatosteatosis and lidocaine metabolism. A study using isolated rat liver perfusion.

The effects of taurine in parenteral nutrition (PN)-related hepatic dysfunction are controversial. The aims of the present study were to evaluate the effects of taurine on hepatic function and on lidocaine metabolism, using two strengths of taurine (15 and 50 mg/dl) that are present in commercially available preparations. Animals (N > or = 4) were randomly assigned to one of the four 7-day treatment groups: chow-fed (CF); dextrose/amino acids (PN); dextrose/amino acids and taurine, 15 mg/dl (T15); dextrose/amino acids and taurine, 50 mg/dl (T50). Between 40-75% of the animals treated with PN developed steatosis. The origin of steatosis was zonal specific and dependent on taurine treatment. All livers in the CF group had a normal cellular architecture. Lidocaine metabolism was found to be impaired in groups PN, T15, and T50. This was indicated by a significant reduction in the intrinsic clearance values: 70%, 76%, and 85% in groups PN, T15, and T50, respectively (p < 0.05). Metabolites-to-drug ratios indicated that N-dealkylation, m-hydroxylation, and aryl methyl hydroxylation were significantly reduced in all treatment groups; the most pronounced effect was observed in the T50 group. These findings suggest that PN infusion results in impaired liver function, and the reduction of drug elimination rate is exacerbated by the addition of taurine.

Amino Acids↗
PubMed1995

Conditioned place preferences, conditioned locomotion, and behavioral sensitization occur in rats treated with diethylpropion.

Diethylpropion is a centrally acting appetite-suppressing drug thought to act primarily through catecholamine pathways in the brain. In the present study, four doses of diethylpropion (0, 10, 20, and 40 mg/kg, intraperitoneally) were administered to rats to examine the hypothesis that the drug has psychomotor stimulant properties such as the ability to induce conditioned behaviors and behavioural sensitization. The rats were administered drug and then vehicle on alternating days, and confined to a "drug" or vehicle-paired side of a two-compartment box for 16 pairings. Only the 10-mg/kg dose of diethylpropion increased spontaneous locomotor activity in comparison to vehicle; the 20- and 40-mg/kg doses significantly decreased spontaneous locomotion. All doses of diethylpropion decreased spontaneous rearing, and the 20-and 40-mg/kg doses produced significantly less rearing than the 10-mg/kg one. At the 10-mg/kg dose, conditioned place preferences, conditioned locomotion, and conditioned rearing were observed. The 40-mg/kg dose produced conditioned rearing and conditioned defecation. In response to a 5-mg/kg challenge injection of diethylpropion, behavioural sensitization in locomotion and rearing occurred in rats that had previously received any one of the three doses of diethylpropion. Over 36 days, decreased weight gain was observed only in the 20- and 40-mg/kg groups. The rats were killed 48 h after the last drug injection, and whole brain was analyzed for levels of the catecholamines, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT (not a catecholamine), and 5-hydroxyindoleacetic acid (5-HIAA) by HPLC with electrochemical detection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Analysis of the enantiomers of 3,4-methylenedioxy-N-ethylamphetamine (MDE, "Eve") and its metabolite 3,4-methylenedioxyamphetamine (MDA) in rat brain.

The methylenedioxy analogues of amphetamine are used recreationally despite concerns raised regarding potential neurotoxicity of the parent compounds and a number of metabolites. Much has been written regarding 3,4-methylenedioxymethamphetamine (MDMA; 3,4-methylenedioxy-N-ethylamphetamine (MDE; "Eve"), despite recent reports indicating the abuse of this drug and its potentially serious side effects. An assay procedure was developed for the simultaneous quantitation of both enantiomers of MDE and its metabolite MDA; the method involves derivatization with an optically pure reagent and analysis on a gas chromatograph equipped with a capillary column and a nitrogen-phosphorus detector. Brain levels of the enantiomers of MDE and MDA were examined in the rat at different time periods after acute i.p. injections of racemic MDE and the results were compared with levels of MDMA and MDA obtained after i.p. injection of MDMA in a previous study from our laboratories. The levels of the enantiomers of MDE and MDA achieved at 1, 4, and 8 hr were lower than in the case of MDMA. Stereoselective differences in brain levels of enantiomers of the parent drug and metabolite were much less marked with MDE than with MDMA, but where these small differences did exist in the case of MDE, the (R)-(-) vs (S)-(+) relationship was opposite to that reported for MDMA.

3,4-Methylenedioxyamphetamine↗
PubMed1995

Simultaneous quantification of fluoxetine, norfluoxetine, and desipramine using gas chromatography with nitrogen-phosphorus detection.

The combination of fluoxetine (FLU) and desipramine (DMI) has been reported to be useful for the treatment of depression, and these drugs are also known to undergo a metabolic drug-drug interaction because of their effects on cytochrome P-450 2D6. A procedure that separates these two drugs and norfluoxetine (NFLU), the N-demethylated metabolite of FLU, and that allows simultaneous quantification of their levels would be of value and has been developed in our laboratories. The procedure involves an initial extraction into ethyl acetate after basification of the homogenate. The organic phase is retained and taken to dryness; the residue is reconstituted in water and acetylated with acetic anhydride under slightly basic conditions. Ethyl acetate is then used to extract the acetylated compounds from the aqueous medium. The organic layer is taken to dryness and the residue reconstituted in toluene. An aliquot of the solution in toluene is injected directly into a gas chromatograph equipped with a nitrogen-phosphorus detector, a fused silica capillary column, and an integrator/printer. Maprotiline is added to the initial homogenate and carried through the procedure as the internal standard. The assay is rapid and sensitive and has been applied successfully to liver and brain tissue taken from rats treated with FLU, DMI, or the combination.

Animals↗
PubMed1994

The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine.

The antidepressant fluoxetine (FLU) and its N-demethylated metabolite, norfluoxetine (NFLU), each contains a chiral center. The combination of FLU and desipramine (DMI), another antidepressant, has been reported to be useful in treatment of depression, to dramatically increase plasma levels of DMI and also to produce more rapid beta-adrenergic receptor down-regulation in brain than caused by DMI alone. We have now begun studies on the effects of this drug combination on the levels of FLU and NFLU enantiomers in the rat. In addition, the combination of FLU and iprindole (IPR) was also investigated. Male Sprague-Dawley rats were treated intraperitoneally with either normal saline vehicle, DMI (5 mg/kg/day), (R,S)-FLU (10 mg/kg/day) or DMI (5 mg/kg/day) + (R,S)-FLU (10 mg/kg/day) for 4 days. Following the last treatment, 24 h urine samples were collected. Rats were sacrificed and brains were removed. For the IPR study, rats were pretreated with either saline or IPR-HCl (11.2 mg/kg) and then treated 1 h later with (R,S)-FLU. After 5 h, the rats were sacrificed and brains were removed. Brain and urine samples were analyzed by gas chromatography with electron-capture detection for free (R)-and (S)-FLU and (R)- and (S)-NFLU after extraction and reaction with (-)-(S)-N-(trifluoroacetyl)prolyl chloride. The results from the brains of the rats treated with DMI/FLU indicate that levels of enantiomers of both FLU and NFLU were significantly increased over those seen in the animals receiving (R,S)-FLU alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: effects on GABAergic function.

The MAO inhibitor phenelzine (2-phenylethylhydrazine; PLZ) is used widely in psychiatry for the treatment of depression and panic disorder. Its N-acetyl metabolite, N2-acetylphenelzine (N2AcPLZ) is a reasonably potent nonselective inhibitor of monoamine oxidase (MAO) that causes elevation in brain levels of the biogenic amines. In the studies reported here, PLZ (0.05 mmol/kg/day), N2AcPLZ (0.10 mmol/kg/day) or vehicle were administered to male rats for 28 days s.c. with Alzet minipumps, and their effects on GABAergic function were examined. Whole brain concentrations of gamma-aminobutyric acid (GABA) were significantly elevated in the PLZ but not in the N2AcPLZ-treated group. PLZ was found to inhibit the anabolic enzyme glutamic acid decarboxylase (GAD) and, to a greater extent, the catabolic enzyme GABA transaminase (GABA-T). The results of these investigations suggest that the free hydrazine moiety in PLZ is crucial to producing the elevated levels of GABA, probably through inhibition of GABA-T. Despite the considerable increase in whole brain GABA levels in the PLZ-treated rats, there were no significant differences in GABAA or benzodiazepine receptor binding parameters (KD or Bmax) between the groups as measured using 3H-muscimol and 3H-flunitrazepam in radioligand binding assays.

4-Aminobutyrate Transaminase↗