ABSTRACT
A sensitive and selective high-performance liquid chromatographic method for the determination of pyrrolidinone (I) in plasma is described. Compound I was extracted from plasma with methylene chloride using kieselguhr as aqueous phase support. The gamma-aminobutyric acid (II) formed after alkaline hydrolysis of I was derivatised with o-phthalaldehyde, chromatographed on a reversed-phase column, and quantified by fluorescence detection. The limit of quantification was 2.5 ng/ml (intra-assay R.S.D. 5%) using a 1-ml plasma sample. The inter-assay precision was 3-14% (R.S.D.) over the concentration range 2000-5 ng/ml, and the recovery from plasma was quantitative (99.3 +/- 2.9%). The accuracy of this method was established from the good agreement between the values obtained after the analysis of plasma samples by both this method and a gas chromatography--mass spectrometry method. The high-performance liquid chromatographic procedure was applied to the determination of (a) endogenous I in human plasma samples and (b) I in plasma following intravenous administration of this substance to a dog. In twelve human subjects, endogenous concentrations of I of 8.3 +/- 2.3 ng/ml (gas chromatography--mass spectrometry method: 6.1 +/- 2.6 ng/ml) were found.
Subject(s)
Pyrrolidinones/blood , Animals , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Dogs , Drug Stability , Gas Chromatography-Mass Spectrometry , Humans , Hydrolysis , Indicators and Reagents , Plasma/analysis , Spectrometry, Fluorescence , o-PhthalaldehydeABSTRACT
2-Pyrrolidinone and succinimide were identified in blood plasma of man, rat, and mouse. Dog plasma contained only traces of 2-pyrrolidinone not exceeding significantly the detection limit of our GCMS-method. Succinimide but not 2-pyrrolidinone could also be found in the brains of rat and mouse. Evidence is presented for a metabolic pathway leading from 2-pyrrolidinone to succinimide, with 5-hydroxy-2-pyrrolidinone as an intermediate.
Subject(s)
Pyrrolidinones/analysis , Succinimides/analysis , Adult , Animals , Biotransformation , Brain Chemistry , Chromatography, High Pressure Liquid , Dogs , Gas Chromatography-Mass Spectrometry/methods , Humans , Mice , Pyrrolidinones/blood , Rats , Succinimides/bloodABSTRACT
The single-dose kinetics of the MAO-inhibitor p-chloro-N-(2-morpholinoethyl)-benzamide (moclobemide, Ro 11-1163) following oral and i.v. administration to six healthy subjects is described. The dosage was 50 mg throughout (1 tablet moclobemide orally, 2.0 ml ampoule moclobemide i.v.). The unchanged drug in plasma was measured by means of an HPLC-assay. The i.v. plasma level curves were analyzed assuming a two-compartment model. The drug was rapidly distributed into the tissue compartment and was then eliminated from the body with a mean half-life t 1/2 beta of about 1 h (range 0.79-1.34 h). The volume of distribution Vss was of medium size (range 0.81-1.25 l/kg). The oral bioavailability was reduced in consequence of the effect of the first passage through the liver and amounted to 44% on average (range 27-70%). As to the drug absorption from the intestinal tract the extent and rate of this process were shown to be large (more than 95% absorbed on average, tmax-values within 1 h).
