Stable Isotopes in Pharmacology Studies: Present and Future

Abstract

Stable-isotope techniques offer advantages over older methods in safety, sensitivity, specificity, and reduction in numbers of subjects required and analytic determinations for some types of pharmacology studies. In addition to their use as internal standards in gas chromatography-mass spectrometry analytic methods, stable isotopes have been successfully employed in studies of absorption, bioavailability, distribution, biotransformation, excretion, metabolite identification, time-dependent and dose-dependent pharmacokinetic changes, drug interactions, pharmacologic changes during pregnancy, mutagenicity, and teratogenicity.

Metabolism and Excretion of an Oral Taxane Analog, [14C]3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxy-paclitaxel (BMS-275183), in Rats and Dogs

“…O, etc. )-labeled drugs can assist in detection and identification of metabolites by mass spectrometry (Baillie et al, 1986(Baillie et al, , 2001Browne, 1986;VandenHeuvel, 1986). The isotopic clusters generated from the mixture of natural and synthetically introduced isotopes can be used efficiently to track and identify drug-related compounds in the complex biological matrices.…”

Applications of stable isotopes in clinical pharmacology

“…In this case, the mass of the labelled molecule is only modestly increased (1.7%). An extreme situation is 2 H2O (heavy water, D2O) in which 100% of the 1 H atoms are replaced by 2 H.The molecular weights of regular water and heavy water are therefore 18 and 20 g mol -1 , respectively; an increase of 11%. Physicochemical properties of heavy water are very different from regular water; for example, the freezing points (3.8 vs. 0.0°C) and the boiling points (101.4 vs. 100.0°C) [3].…”

“…As the mass of 2 H is twice that of 1 H, labelling may lead to large differences in metabolic handling, depending on the reactivity of the position of 2 H in the molecule. Lewis investigated the effect of 2 H2O on the development of seedlings from tobacco seed.…”

“…Since then, several groups have used stable isotope technology in their clinical pharmacological studies, especially those led by M. Eichelbaum and T. R. Browne. Their work has stimulated stable isotope technology to obtain a distinct place in clinical pharmacology in the 1980s; however, the most recent review paper on the all applications of stable isotopes in (clinical) pharmacology is over 20 years old [2]. Three main categories of stable isotope technology can be distinguished in clinical pharmacology (Table 1).…”

Quantitative analysis with modern bioanalytical mass spectrometry and stable isotope labeling

“…One of the first surveys on the applications of stable isotopes in drug metabolism studies was carried out by Baille, 81 followed by three reviews by Browne,82,83 Pons and Rey, 84 and Abramson. 85 Although these reviews are now dated and looked at selected aspects such as the economics of drug development, pediatric clinical pharmacology, and drug metabolism, they summarized the main uses of stable isotope labeling studies in mass balance and general ADME studies.…”