Metabolic switching of drug pathways as a consequence of deuterium substitution

Both in vivo and in vitro isotope effects have been observed when deuterium was substituted for hydrogen in a chemical bond that is involved in an enzymatic reaction. In a recent review Blake et al. (1) have summarized the studies that have been carried out with deuterated drugs and Tomaszewski et dl. (2) have discussed their studies on the deuterium isotope effects observed during the formation of phenolic metabolites. Changes in both pharmacological activity and biological half-life have been reported but marked alterations in the pathway of metabolism of the deuterated compounds were apparently not observed. However, several of the drugs investigated were metabolized sequentially, that is, by hydroxylation and subsequent conjugation rather than by multiple alternate pathways If a drug is metabolized by multiple alternate pathways, rather than sequentially, the metabolism may be shifted by deuterium labeling. For example, in recent studies by Cox et at. (3), the metabolism of cyclophosphamide, 4,4-dideutero- and 5,5-dideuterocyclophosphamide was compared. Substitution of two deuteriums in the 5- position depressed the S-elimination reaction leading to phosphoramide mustard, the cytotoxic metabolite. As a result, the metabolism of the 5,5-dideutero analog was shifted to alternate pathways and the inactive metabolites were formed. In our laboratory we have investigated the metabolism of deuterated analogs of caffeine (l-CD3-caffeine and 7-CD3-caffeine) and antipyrine (N-CD3-antipyrine and 3-CD3-antipyrine) because both caffeine and antipyrine are metabolized by multiple alternate pathways. Since it is well established that carbon-deuterium bonds are more stable than carbon-hydrogen bonds, it was postulated that oxidation of the -CD3 group would be depressed and that metabolism of the labeled compounds would be shifted to another pathway that did not involve cleavage of a carbon-deuterium bond. Metabolic switching of drug pathways was observed in vivo for both of the caffeine analogs and was observed both in vivo and in vitro for 3-CD3-antipyrine.