Stable isotopes drug metabolism

Studies on Drug Metabolism Using Stable Isotopes. I. Metabolism of 31252-S-d5... 

B. Vogelgesang, H. Echizen, E. Schmidt, and M. Eichelbaum, Stereoselective first-pass metabolism of highly cleared drugs Studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique, Br. /. Clin. Pharmacy.. 18 733-740 (1984). 

Systemic bioavailability is the product of fraction of dose absorbed (/a), fraction of dose escaping gut metabolism (/g), and fraction of dose escaping first-pass metabolism (F ). Permeability class is based upon /a, which may be estimated either in vivo or in vitro by direct measurement of mass transfer across human intestinal epithelium. In vivo methods include (i) mass balance studies using unlabeled, stable-isotope labeled, or a radiolabeled drug substance (ii) oral bioavailability using a reference intravenous dose or (iii) intestinal perfusion studies either in humans or an acceptable animal model. Suitable in vitro methods involve the use of either excised human/animal intestinal tissues or cultured epithelial monolayers. All of these methods are deemed appropriate for drugs whose absorption is controlled by passive mechanisms. 

This review is intended to survey those uses of stable isotopes which are of particular importance in medicinal chemistry. These include their use in 1) structure elucidation, 2) studies of drug metabolism, 3) pharmacokinetic analysis and 4) drugs used in therapy. The use of stable isotopes for investigating intermediary metabolism, and their rapidly expanding use in clinical chemistry will not be reviewed since these topics have been covered elsewhere. Synthesis and biosynthesis with stable isotopes have also been previously surveyed >10 and many articles appear in each issue of the Journal of Labelled Compounds and a few have appeared in Biomedical Mass Spectrometry in the past year. In addition, one recent article has appeared on the use of plants to continously produce stable isotope labeled compounds of pharmacological interest. ... 

III. Use of Stable Isotopes in Studies of Drug Metabolism and Toxicology -Since the advent of mass spectrometry (ms) coupled with gas chromatography (gc-ms), stable isotopes have been used extensively in the study of drug metabolism. The use of ms in the field of drug metabolism has been reviewed, 29,30 an(j t0th reviews cover the use of stable isotopes. There are several ways in which stable isotopes have been used to study drug metabolism and these will be covered individually. 

Atoms that have the same atomic number (Z) but different atomic mass numbers (A) are termed isotopes [1]. Isotopes are classified into atoms that are unstable and decay by emission of radiation to stable products (radioisotopes) and those that have never been observed to decay (stable isotopes). Most of the elements associated with organic compounds possess naturally occurring stable isotopic variants. Stable isotopes frequently encountered in the course of pharmacokinetic and drug-metabolism studies and their natural abundances, relative to the most abundant mass, are listed in Table 1 [2,3]. 

With this brief background on stable isotopes and the principles behind their detection, this chapter attempts to provide a window to some unique applications of stable isotopes in pharmacokinetic and drug metabolism studies. These and additional applications have been subjects of some excellent reviews that provide more elaborate discussions of the use of stable isotopes in research [4—13,18]. The emphasis, for obvious reasons, is placed on applications that utilize mass spectrometry as the analytical method. The applications are given below, followed by a brief discussion of each application and considerations involved therein. 

TA Baillie, AW Rettenmeier. Recent advances in the use of stable isotopes in drug metabolism research. J Clin Pharmacol 26 481 -84, 1986. 

DR Hawkins. The role of stable isotopes in drug metabolism. In JW Bridges, LF Chasseaud, eds. Progress in Drug Metabolism. Bristol, UK Wiley, 1977, pp 163—218. 

FP Abramson, Y Teffera, J Kusmierz, RC Steenwyk, PG Pearson. Replacing 14C with stable isotopes in drug metabolism studies. Drug Metab Disp 24 697-701, 1996. 

Chowdhury, S.K. et al., Detection and characterization of highly polar metabolites by LC-MS Proper selection of LC column and use of stable isotope labeled drug to study metabolism of rabavirin in rats, in Identification and Quantification of Drugs, Metabolites and Metabolizing Enzymes by LC-MS, Chowdhury, S.K. (ed.), Elsevier, Amsterdam, the Netherlands, 277, 2005. 

Baillie, T.A. et al., Mechanistic studies on the reversible metabolism of rofecoxib to 5-hydroxyrofecoxib in the rat Evidence for transient ring opening of a substituted 2-furanone derivative using stable isotope-labeling techniques, Drug Metab. Dispos., 29(12), 1614, 2001. 

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