Stable isotopes in drug metabolism and pharmacokinetics

The metabolic pathways of alprenolol have been investigated in man and the dog, using an ion doublet technique of deuterium labelling combined with gas chromatography mass spectrometry. The drug is eliminated mainly by aromatic hydroxylation and glucuronidation. Specific analytical methods are applied to demonstrate that allylic oxidation and oxidative deamination are quantitatively of minor importance. The mechanism for oxidative deamination via an intermediary aldehyde could be elucidated by using the deuterium labelled compound. A method for characterization of 4-hydroxy-alprenolol glucuronides based on formation of stable derivatives and the following enzymatic hydrolysis is described. This approach has a general applicability to hydroxylated metabolites from compounds with an aminopropanol structure common for beta-adrenoceptor antagonists, for example. The metabolic routes for alprenolol in man and the dog are almost identical and in man more than 95% of a given dose can be accounted for.

Study of the metabolic pathways of alprenolol in man and the dog using stable isotopes

Hoffmann¹,

Arfwidsson²,

Borg³

et al. 1978

Radiogas chromatography mass spectrometry in the selected ion monitoring mode

Doerfler

Rosenblum

Malloy

et al. 1980

The value of selected ion monitoring in analyzing biological radio isotope incorporation experiments by radiogas chromatography mass spectrometry is illustrated with reference to the biosynthesis of the mycotoxin mycophenolic acid and the mode of action of the anticholesterolemic drug 20,25-diazacholesterol. It is shown that the increased sensitivity and specificity of the selected ion monitoring mode detector permits straightforward detection and identification of the relatively small cellular pools associated with metabolic intermediates. The computer program RADSIM is described. Problems that still exist in using radiogas gas chromatography mass spectrometry technology to analyse isotope incorporation experiments are discussed.

The use and limitations of deuterated lorcainide in metabolism and pharmacokinetic studies

Gelijkens

Peer

Lenoir

et al. 1985

Lorcainide, a new antiarrhythmic agent currently undergoing clinical trial, has been pentadeuterated and the usefulness of this labelled compound in pharmacokinetic and metabolism studies has been investigated in dogs. Specific analytical methods based on capillary gas chromatography/mass spectrometry (GC/MS) were developed for quantitative and qualitative analysis of plasma and urine samples. Following oral administration of an equimolar mixture of 5 : 5 mg of (2H0/2H5)lorcainide, eight major metabolites were rapidly identified in urine by the ion cluster technique. Quantitative analysis of (2H0/2H5)lorcainide in plasma and urine indicated an enhanced systematic availability of the deuterated compound, probably due to a secondary isotope effect. According to these findings in the dog, the use of deuterated lorcainide in human bioavailability and metabolism studies is probably of limited value.