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Biomedical subjects

O Grech-Bélanger

Publications and source records attributed to O Grech-Bélanger.

10 recordsLinked to original sources
PubMed1991

Resolution and electrophysiological effects of mexiletine enantiomers.

Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p-toluoyl tartrate salts. Following three crystallization steps in methanol, R-(-)- and S-(+)-mexiletine were resolved with an optical purity greater than 98% (yield approximately 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally-induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7-30 days after coronary ligation. R-(-)-Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0.5 mg kg-1, 1 after 8 mg kg-1); two animals died after 1 and 8 mg kg-1, respectively; one remained unchanged even at the highest dosage (16 mg kg-1). S-(+)-Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg-1); two died after 4 and 8 mg kg-1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg-1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0.5-16.0 mg kg-1). These results suggest that R-(-)-mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.

Animals↗
PubMed1991

Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man.

Mexiletine is a low clearance drug which undergoes extensive metabolism in man. In vitro studies with human liver microsomes have suggested that major oxidation pathways of mexiletine are predominantly catalyzed by the genetically determined debrisoquine 4-hydroxylase (cytochrome P450IID6) activity. In this study, we investigated the role of debrisoquine polymorphism and the effects of low dose quinidine, a selective inhibitor of cytochrome P450IID6, on the disposition of mexiletine. Fourteen healthy volunteers, 10 with the extensive metabolizer (EM) and 4 with the poor metabolizer (PM) phenotype, received a single 200-mg dose of mexiletine hydrochloride orally on two occasions (1 week apart), once alone and once under steady-state conditions for quinidine (50 mg QID). During the phase mexiletine alone, total clearance, nonrenal clearance and partial metabolic clearance of mexiletine to hydroxymethylmexiletine, to m-hydroxymexiletine and to p-hydroxymexiletine were decreased in PM compared to EM (all P less than .05). In EM, quinidine decreased mexiletine total clearance from 621 +/- 298 to 471 +/- 214 ml/min (mean +/- S.D.; P less than .05) and mexiletine nonrenal clearance from 583 +/- 292 to 404 +/- 188 ml/min (P less than .05). Moreover, quinidine increased mexiletine elimination half-life in EM from 9 +/- 1 to 11 +/- 2 h (P less than .05). In these subjects, partial metabolic clearance to hydroxymethylmexiletine, m-hydroxymexiletine and p-hydroxymexiletine were decreased by quinidine coadministration 5-, 4- and 7-fold, respectively, whereas partial metabolic clearance to N-hydroxymexiletine was unaffected. Changes induced by quinidine in EM were correlated to their debrisoquine metabolic ratio. Thus, genetically determined or pharmacologically induced modulation of cytochrome P450IID6 activity represents a major determinant of mexiletine disposition.

Administration, Oral↗
PubMed1989

Pharmacokinetics of mexiletine in the elderly.

The effect of advancing age on the kinetics of the antiarrhythmic agent mexiletine was studied by comparing various kinetic parameters calculated after administration of a single oral dose of mexiletine hydrochloride to seven elderly and eight young healthy volunteers. The rate of absorption of the drug from the gastrointestinal tract was significantly slower in the elderly (1.37 +/- 0.51 hr-1) than in the young group (2.25 +/- 0.79 hr-1). The mean values for elimination half-life and oral clearance were 12.3 +/- 3.7 hr and 10.3 +/- 5.4 mL/min/kg respectively in the young group and 14.4 +/- 4.5 hr and 8.5 +/- 2.9 mL/min/kg respectively in the elderly group. Neither of these parameters was significantly different between the two groups. The amount of mexiletine eliminated in urine up to 48 hours postdose was identical in both groups and represented less than 5% of the administered dose. It is concluded that the age-related modifications in the kinetics of mexiletine are not clinically important during chronic administration of the drug.

Adult↗
PubMed1989

The effect of fleroxacin on hepatic drug metabolism in the rat.

Pretreatment of rats with repeated i.p. doses of fleroxacin had no effect on the hepatic O- and N-demethylation of p-nitroanisole (PN) and aminopyrine (A) respectively, on the p-hydroxylation of aniline or on the hepatic levels of cytochrome P-450 and protein content. Addition of fleroxacin directly to incubation mixtures reduced PN O-demethylase activity significantly but did not affect the other two oxidative reactions. The N-oxide metabolite increased PN O-demethylation by 16% whereas the N-demethylated metabolite decreased the N-demethylation of A by 10%. Concomitant administration or pretreatment with fleroxacin had no effect on antipyrine's elimination kinetic parameters.

Animals↗
PubMedDate not supplied

Isolation and structural characterization by spectroscopic methods of two glucuronide metabolites of mexiletine after N-oxidation and deamination.

Urine samples from control and mexiletine-treated human subjects or rabbits (test group) were collected and passed through an ion exchange resin to isolate polar compounds. Methanolic eluates from control and test urines were analyzed by TLC. Exposure to p-dimethylaminocinnamaldehyde gave an additional intense pink band at Rt 0.40-0.45 in TLC analysis of test urine eluate when compared to control urine eluate. Non-exposed silica at this Rt was scraped and metabolites were extracted with methanol. Hydrolysis of this methanolic extract at 100 degrees C with hydrochloric acid released mexiletine. GC/MS and fast atom bombardment mass spectrometry analyses of nonhydrolyzed methanolic extracts evidenced the presence of two conjugated metabolites of mexiletine, namely, N-hydroxymexiletine glucuronide and mexiletine alcohol glucuronide. Synthetic compounds corresponding to these metabolites were obtained and spectra compared with those of isolated metabolites from urine. Definite structure assignment of N-hydroxymexiletine glucuronide was obtained from NMR spectrometry which confirmed the structure to be a hydoxylamine glucuronide (N-O-C link) and showed that the glycoside moiety was in the beta configuration. Thus, it is proposed that N-hydroxymexiletine glucuronide corresponds to mexiletine acid-labile conjugate and represents a major metabolic pathway in the disposition of mexiletine.

Animals↗
PubMedDate not supplied

Meta-hydroxymexiletine, a new metabolite of mexiletine. Isolation, characterization, and species differences in its formation.

Meta-hydroxymexiletine [1-(3-hydroxy,2,6-dimethyl)phenoxy-2-amino-propane], a novel metabolite of the antiarrhythmic drug mexiletine, was isolated from urine of rats given mexiletine. The structure of the metabolite was elucidated by 1H-NMR and mass spectrometry and by IR spectrophotometry. The metabolite is produced in vitro by hepatic microsomes of various laboratory animals including rat, guinea-pig, hamster, rabbit, and mouse. In humans, meta-hydroxymexiletine accounts for approximately 2% of the administered dose of mexiletine.

Animals↗
PubMedDate not supplied

Deacetylation of diltiazem by rat liver.

The enzyme system mediating the hydrolysis of the calcium antagonist diltiazem to give deacetyldiltiazem was characterized in the rat. Tissue distribution studies showed that the highest level of activity was mainly localized in the microsomal fraction of the liver. Some activity was also detected in the red blood cells. The kinetics of the enzymatic reaction demonstrated that the formation of deacetyldiltiazem increased linearly with time up to 60 min and with protein content up to 7.8 mg. Apparent Km and Vmax values calculated from a Lineweaver-Burk plot were 0.17 X 10(-3) M and 0.013 mumol/mg of protein/min. Mercuric chloride, silver nitrate, and cupric chloride at concentrations of 0.6 X 10(-3) M decreased the diltiazem deacetylase activity to 47%, 24%, and 19%, respectively, as compared to control incubations. At a concentration of 6.7 X 10(-8) M, cadmium sulfate decreased the hydrolysis of diltiazem by 40%, whereas cobaltous sulfate at concentrations of 10(-3) M did not affect the deacetylation activity. The hydrolysis reaction was depressed by the organophosphorus compounds, bis-p-nitrophenylphosphate and diisopropyl fluorophosphate to 31% and 0%, respectively, at concentrations of 10(-6) M. Eserine sulfate at a concentration of 2.2 X 10(-4) M, and disulfiram and aspirin at concentrations of 10(-3) M decreased the diltiazem deacetylase activity to 17%, 71%, and 79%, respectively. Rifampicin and phenacetin at concentrations of 10(-3) M did not inhibit the hydrolysis reaction. In vivo pretreatment of the rats with phenobarbital increased the in vitro diltiazem deacetylase activity 3.2-fold, whereas 3-methylcholanthrene did not affect the enzymatic hydrolysis of diltiazem.

Amidohydrolases↗
PubMedDate not supplied

Metabolic reduction of 1-nitrosoadamantane by rabbit liver microsomes. Properties of a C-nitroso reductase system.

Washed microsomes from rabbit liver reduced 1-nitrosoadamantane to N-hydroxy-1-aminoadamantane in the presence of a cofactor solution under aerobic conditions; no further reduction of the hydroxylamino metabolite to 1-aminoadamantane (amantadine) occurred. Reduced pyridine nucleotide cofactors are needed for the metabolic reduction. The rate of formation of N-hydroxy-1-aminoadamantane depended upon the microsomal protein content, the time of incubation and the concentration of 1-nitrosoadamantane incubated. The metabolic reduction occurred in air as well as under nitrogen or carbon monoxide. Cupric chloride, mercuric chloride, cysteamine, FAD, and FMN decreased significantly the C-nitroso reductase. The properties of the C-nitroso reductase differed from those of other microsomal reductive pathways.

Adamantane↗