3-(2,6-Xylyl)-5-methylhydantoin--a metabolite or a metabonate of tocainide in rats

1. G.1.c.-mass spectrometric analysis of urine extracts from rats dosed with tocainide (I) revealed the presence of cyclic compound identified as 3-(2,6-xylyl)-5-methylhydantoin (IV) derived from tocainide. 2. Evidence indicates that IV is derived from a conjugate of tocainide (tocainide carbonyl O-beta-D-glucuronide) (III) in humans. 3. Results of the present study indicate that in addition to being formed from a conjugate, IV is generated directly from tocainide in vivo in rats. Possible mechanisms for the formation of IV in rats in vivo are discussed.     

The pharmacology of 1-(2-pyrimidinyl)piperazine, a metabolite of buspirone

In experiments on rats the anxiolytic activity of 1-(2-pyrimidinyl)-piperazine (PP) was revealed only in some models of anxiety states, although diazepam was effective in all used models. In contrast to diazepam, PP exerts the anesthetic-potentiating and myorelaxant effects only when administered in subtoxic doses and possesses no anticorazole activity. The facts testifying to the serotoninergic mechanisms of the anxiolytic action of 1-(2-pyrimidinyl)-piperazine are presented.     

The origin of 1-(3-pyridyl-N-oxide)ethanol as a metabolite of 3-acetylpyridine

1. 3-Acetylpyridine was metabolized extensively to 1-(3-pyridyl)ethanol when the hepatic enzyme source was the soluble fraction (140 000g supernatant). 3-Acetylpyridine-N-oxide was identified as a metabolite using the 10 000g or the microsomal fraction.

2. 1-(3-Pyridyl-N-oxide)ethanol was not detected as a metabolite of 1-(3-pyridyl)ethanol using tissue preparations. However, 3-acetylpyridine was formed in trace amounts when the alcohol was incubated with the 10 000g or the microsomal fraction.

3. Incubation of 3-acetylpyridine-N-oxide with the soluble or 10 000g fraction resulted in the formation of 1-(3-pyridyl-N-oxide)ethanol (keto-reduction) as the major metabolite. 3-Acetylpyridine was formed in trace amounts (N-oxide reduction) with the 10 000g and the microsomal fractions.     

1-(ℴo-Methoxyphenyl)piperazine is a metabolite of drugs bearing a methoxyphenylpiperazine side-chain

Drugs bearing an o-methoxyphenylpiperazine (oOCH₃PP) moiety in the side-chain of their molecule may form oOCH₃PP during biotransformation in-vivo in the rat. This has been verified by combined gas chromatography-mass spectrometry of urine from rats given orally a series of relatively new o-methoxyphenylpiperazine-substituted derivatives. The metabolite is reported to be biochemically and pharmacologically active and therefore its formation may have pharmacological significance, at least for derivatives undergoing extensive cleavage of the arylpiperazine side-chain.     

Presence of a diffusional barrier on metabolite kinetics: enalaprilat as a generated versus preformed metabolite

Studies in the once-through perfused rat liver with the simultaneous delivery of 14 C-enalapril and its polar diacid metabolite, 3H-enalaprilat, revealed different extents of elimination (exclusively by biliary excretion) for the generated (14C-enalaprilat) and preformed (3H-enalaprilat) metabolite (18 and 5% dose) [Pang, Cherry, Terrell, and Ulm: Drug Metab. Dispos. 12, 309-313 (1984)]. The present re-examination of data provided an explanation for these discrepant observations: enalaprilat, being a polar dicarboxylic acid, encounters more of a diffusional barrier than its precursor, enalapril, an ethyl ester of enalaprilat. Programs written in Fortran 77 on mass balance relationships were employed to simulate data upon varying the diffusional clearances for drug (CLd) and metabolite [CLd(mi)] from 1 to 5000 ml/min. The metabolic and biliary intrinsic clearances for drug and metabolite were found by trial and error such that the combinations of all clearance parameters yielded data similar to enalaprilat, and 3H-enalaprilat. Our finding indicated that the diffusional clearance for enalaprilat was low (2 ml/min) compared to that of enalapril (75 ml/min). The presence of a diffusional barrier for enalaprilat retards entry of the preformed metabolite into hepatocytes but prevents efflux of the intracellularly formed generated metabolite into sinusoidal blood, thereby enhancing generated metabolite elimination.     

Disposition of (-)-fenfluramine and its active metabolite, (-)-norfenfluramine in rat: a single dose-proportionality study

1. The disposition of (-)-fenfluramine, (-)-F, was studied in rats after i.v. and oral administration (1.25 to 12.5 mg/kg). Whole blood-to-plasma ratio and the protein binding (determined by equilibrium dialysis) of the compound and its main active metabolite, (-)-norfenfluramine (-)-NF, were investigated. 2. The bound fraction of both compounds (about 40%) was constant in the concentration range of 1-10 nmol/ml. The whole blood to plasma concentration ratios of (-)-F and (-)-NF were larger than unity and were constant over this dose range. 3. The drug followed apparent first-order kinetics, at doses up to 6.25 mg/kg. The mean half-lives of the parent drug and its metabolite were about 1 and 12 h respectively. The volume of distribution of (-)-F was large and total body clearance approached liver blood flow. 4. Oral doses were rapidly absorbed from the rat gastrointestinal tract. Bioavailability of the drug was about 20%. Urinary excretion of unchanged drug (3-4% of dose) and its metabolite (about 20%) were similar after i.v. and oral administration. 5. After larger doses (12.5 mg/kg) the kinetics of (-)-F were nonlinear. The AUC increased, but not in proportion to the dose, and kinetic parameters were modified. 6. Brain concentrations reflected the dose-related changes observed in (-)-F and (-)-NF blood concentrations, and patterns of brain distribution and subcellular localization of the drug and its metabolite were modified at the highest dose tested.