Inhibitory effects of propafenone on the pharmacokinetics of caffeine in humans.

CYP1A2 is involved in the metabolism of both caffeine and propafenone, a class Ic antiarrhythmic agent. Despite the widespread consumption of caffeine, drug-drug interactions with this agent are often overlooked. This study investigated effects of propafenone on the pharmacokinetics of caffeine.

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.

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.

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.

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.

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.

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.

Pharmacokinetics of diltiazem in patients undergoing continuous ambulatory peritoneal dialysis.

The disposition of a single oral dose of diltiazem hydrochloride was studied in six male patients treated by continuous ambulatory peritoneal dialysis. Peak concentrations were obtained 2 to 4 hours postdose. The mean absorption rate constant was 0.

2,6-Dimethylphenol: a new metabolite of mexiletine.

A new metabolite, 2,6-dimethylphenol obtained by O-dealkylation of mexiletine by rabbit liver was identified. A g.c.

Assay of diltiazem and deacetyldiltiazem by capillary gas chromatography.

A highly sensitive gas chromatographic method for the analysis of diltiazem and deacetyldiltiazem in plasma or serum is reported. After silylation with bis (trimethylsilyl) trifluoroacetamide, separation was obtained on a cross-linked fused-silica column and detection was by electron-capture. The minimum measurable concentrations were 3 and 1 ng/ml for diltiazem and deacetyldiltiazem, respectively.

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.

Stereoselective disposition of mexiletine in man.

The pharmacokinetics of S-(+)- and R-(-)-mexiletine and of the corresponding conjugates were investigated in six healthy young volunteers after administration of a single 200 mg oral dose of racemic mexiletine hydrochloride. The values for the distribution rate constants as well as for the elimination half-lives of the two enantiomers were similar but the AUC of the S-(+)-enantiomer was always significantly higher (P less than 0.01) than that of the opposite enantiomer.

Effect of cigarette smoking on mexiletine kinetics.

The effect of cigarette smoking on the kinetics of a single, 200 mg, oral dose of the antiarrhythmic drug mexiletine was investigated in healthy subjects. Cigarette smoking had no effect on absorption or distribution of the drug, but it significantly reduced the elimination t1/2 from 11.1 +/- 3.

High pressure liquid chromatographic assay for mexiletine in serum.

A highly sensitive, rapid, and specific high pressure liquid chromatographic assay for the analysis of the antiarrhythmic agent mexiletine is reported. The method involves extraction of mexiletine with organic solvent followed by analysis using fluorescence detection. The minimum measurable limit is 1 ng and inter- and intra-day coefficients of variation are less than 5.

Depressive effect of amiodarone on hepatic drug metabolism in the rat.

The effect of pretreatment of rats with three daily i.p. doses of 25, 50 and 100 mg/kg of the antiarrhythmic agent, amiodarone, on the activity of some hepatic drug metabolizing enzymes, on the levels of cytochromes P-450 and b5 as well as on lipid peroxidation is reported.

Inhibitory effect of isoniazid on antipyrine clearance in man.

The effect of both concomitant administration and pretreatment with isoniazid on the activity of the hepatic drug-metabolizing enzymes of healthy young volunteers, as indicated by the antipyrine clearance test, is reported. Concomitant administration of isoniazid with antipyrine results in a significant decrease in the hepatic clearance of the latter compound. In contrast, pretreatment for 14 days with isoniazid had no effect on antipyrine elimination kinetics.

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.