Deuterium labelled drugs

At about the same time, a method was described for measurement of nortriptyline in plasma based on dilution with the deuterium-labelled drug... 

For drugs which do not contain these elements isotope doublets can be artificially generated using equimolar mixtures of unlabelled and and/or deuterium-labelled drug (13, 14). The... 

Patel JM, Gordon WP, Nelson SD, et al. 1983. Comparison of hepatic biotransformation and toxicity of allyl alcohol and deuterium-labeled allyl alcohol in rats. Drug Metab Dispos 11 164-166. 

The metabolism and pharmacology127,128 of sodium zomepirac 130, a non-narcotic analgesic drug used in the treatment of mild to moderately severe pain, as well as the synthesis of deuterium labelled 130 in the chlorobenzoyl group129, have been described previously. 

Walle, T. (1985). Stereochemistry of the in vivo disposition and metabolism of propranolol in dog and man using deuterium-labeled pseudoracemates. Drug Metab. Disp., 13 279-282. 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

Although the use of deuterium in drug metabolism involving the isotope cluster technique may be complicated by isotope effects, both cost and convenience have led most workers to rely on this isotope. Recent examples include reports on aminopyrine,pencycuron, phencyclidine, fentanyl, and diethylstilbestrol. In the case of steroids and their derivatives, ion cluster studies have been performed exclusively with deuterium-labeled substrates. Examples include investigations with [ HsJethynylestradiol,[ H2]4-hydroxyandrost-4-ene-3,17-dione, ]-ursodeoxycholic acid, " and [ Jbudesonide. ... 

Where preparation of stable-isotope-labeled drug metabolites is required, an economical approach is to administer the labeled drug to a suitable animal species and to isolate the corresponding labeled metabolites from urine samples. Deuterium-labeled metabolites of antipyrine were obtained in this manner, while deuterated metabolites of 6-oxo-PGF] a were prepared by incubation of the labeled parent prostaglandin with Mycobact erium rhodochrous. ... 

Nelson, W.L. Shetty, H.U. Stereoselective oxidative metabolism of propranolol in the microsomal fraction from rat and human liver. Use of deuterium labeling and pseudoracemic mixtures. Drug Metab. Dispos. 1986,14, 506-508. 

Defoy, D., Dansette, P.M., Neugebauer, W., Wagner, J.R., Klarskov, K. (2011) Evaluation of Deuterium Labeled and Unlabeled Bis-methyl Glutathione Combined with Nanoliquid Chromatography-Mass Spectrometry to Screen and Characterize Reactive Drug Metabolites. Chem. Res. Toxicol. 24 412-417. 

Metabolic switching has been reported as a consequence of deuterium labelling where a drug is metabolised by multiple alternate pathways rather than sequentially [20,21]. Both in vivo studies in rats and in vitro studies using rat... 

By incorporation of a known percentage of a stable isotope labelled drug (normally deuterium, carbon-13, nitrogen-15, or oxygen-18) the relevant metabolites can readily be detected in a biological isolate, without the need for extensive... 

The use of deuterated pharmaceuticals to study intermediary drug metabolism with GC—MS analytical techniques has increased enormously in the last decade and has been discussed in a previous section. Quantitative isotope mass spectrometry may well come into its own in this field in the near future for general screening. Whilst individual metabolites cannot be monitored, the total deuterium excreted in the urine can be accurately measured and thus provide a good indication of the excretion time course of total deuterium label. 

The application of internal standards (IS) is essential for recovery experiments in method development and validation, as well as for the accurate quantification of target analytes. When a mass spectrometer is used, the most appropriate IS is an isotope-labeled derivative of the analyte, as it has the same physicochemical properties but a different nominal mass. Isotope-labeled derivatives of drugs of abuse are preferred in clinical, toxicological, and forensic analyses, but they are very expensive and often difficult to obtain. Shaikh and Chen [99] reported on the synthesis of deuterium-labeled controlled drugs, including tropane alkaloids, having a main focus on GC-MS analyses. 

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