Issue Date: September 7, 2009
A Deuterated Drug That Almost Succeeded
Thank you for Amanda Yarnell's "Heavy-Hydrogen Drugs Turn Heads, Again" (C&EN, June 22, page 36). The notion of deuterating drugs is neither new nor frivolous. Here's a story from the 1970s of Merck's MK0641/MK0642, an antibacterial combination of 2-deutero-3-fluoro-d-alanine (MK0641) and pentizidone (MK0642), a prodrug adduct of d-cycloserine with acetylacetone. This combination made it all the way into Phase II before succumbing.
Fluoro-d-alanine (3FDA) is metabolized by d-amino acid oxidase (DAO) in kidney and liver to 3-fluoropyruvate, which then undergoes oxidative defluorination. The acute toxicity of this drug is very low and attributable to liberated fluoride. The rationale for deuteration was reduction in fluoride generation. Deuteration did reduce primary metabolism: A kinetic isotope effect of 2.8 was observed with DAO in vitro. However, in the more relevant case of open-system metabolism and elimination in vivo, a twofold reduction in fluoride production was found relative to 3FDA.
Reducing MK0641's metabolism became crucial when chronic studies in rats and monkeys revealed intramyelinic vacuolation confined to the corpus callosum. The histopathology resembled that found throughout the brain in infants and burn patients exposed to topical hexachlorophene. The causative agent was determined to be 3-fluorolactate, which is in equilibrium with 3-fluoropyruvate during metabolism (Drug Metab. Dispos. 1986, 14, 668). Our goal was to keep 3-fluorolactate during treatment in man to one-tenth of the levels inducing vacuolation in animals.
Everything went well in Phase I with healthy volunteers, but the first trial with the intended beneficiaries, sick people, proved our undoing. Patients with chronic obstructive pulmonary disease sustained double the anticipated levels of 3-fluorolactate, presumably reflecting a more reduced state of electron transport. The project was abandoned, leaving the consolation that even higher levels would have been sustained with undeuterated 3FDA.
This tale should not discourage deuteration where the objective is reducing primary metabolism alone to produce, for example, greater half-life or reduce intermediary metabolites. However, a necessary requirement for such a goal is an escape pathway, such as renal excretion, for the bulk of the administered dose. In the extreme case of a drug that undergoes complete metabolism, deuteration simply postpones the damage from sooner to later.
Fred M. Kahan
Scotch Plains, N.J.
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