Drug metabolism deuterium isotope effect

For a more detailed and extensive exposition of the use of deuterium isotope effects, including other experimental designs, in drug metabolism studies the interested reader is referred to a recent review article and the references therein (7). 

Nelson SD, Trager WF. The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab Dispos 2003 31(12) 1481—1498. 

Deuterium isotope effects in the metabolism of drugs and xenobiotics Implications for drug design, 14, 1... 

Where isotopically labelled compounds are employed as tracers, biological isotope effects may be encountered. There have been several reports of primary isotope effects in the metabolism of deuterated drugs (for review see [403] and in general, metabolic rate is slower when a bond to deuterium rather than to hydrogen is cleaved during metabolism. Such effects have been observed, for example in the hydroxylation of butobar-bitone [404] and in the JV-demethylation of morphine [405]. A marked deuterium isotope effect has been reported in the 3-hydroxylation of cotinine-d2 (27). In this case a kn/ko ratio of about 6 was determined by... 

Other common pathways of drug metabolism include oxidative 0- and N-dealkylation. Deuterium isotope effects gf — 2 have been observed for the... 

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... 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

Keefer LK, Streeter AJ, Leung LY, et al. 1987. Pharmacokinetic and deuterium isotope effect studies on the metabolism of formaldehyde and formate to carbon dioxide in rats in vivo. Drug Metab Dispos 15 300-304. 

If bond breaking occurs during the rate-determining step of the reaction, then the overall reaction will be slowed by the replacement of hydrogen with deuterium. This is an example of a kinetic isotope effect. The use of deuterium as a bioisostere to manipulate rates of metabolism is a fairly new idea in drug discovery. If SD-254 successfully reaches the market, additional deuterated drugs will almost certainly be advanced into clinical trials. 

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. ... 

---