INHIBITION OF DIHYDROPYRIMIDINE DEHYDROGENASE BY 5-PROPYNYLURACIL, A METABOLITE OF THE ANTI-VARICELLA ZOSTER VIRUS AGENT NETIVUDINE

Objective: To study the effects of the anti-herpetic drug netivudine o n dihydropyrimidine dehydrogenase activity in elderly volunteers and t o relate them to concentrations of netivudine and its metabolite 5-pro pynyluracil. Methods: Three groups of eight elderly volunteers receive d 400 or 800 mg netivudine or placebo once daily for 8 days. Plasma ne tivudine, 5-propynyluracil, and uracil, an indirect measure of dihydro pyrimidine dehydrogenase activity, were assayed before the first dose and on days 2, 3, 5, 7, and 8, Pull plasma profiles of netivudine and 5-propynyluracil were determined after the last dose.Results: Plasma u racil was unquantifiable in all subjects before the first dose and at all time points in the placebo group, In recipients of netivudine it r eached a plateau between days 3 and 5, with mean values of 23.2 and 23 .5 mu mol/L on day 8 in the subjects who received 400 and 800 mg, Plas ma netivudine concentrations were approximately dose proportional, but 5-propynyluracil concentrations were similar in both groups, The half -maximal rise in plasma uracil occurred after a cumulative 5-propynylu racil exposure of 120 mu mol/L . hr; such exposures will be achieved e ven after doses as low as 50 to 100 mg daily, Conclusions: Netivudine dosing produces complete inhibition of plasma dihydropyrimidine dehydr ogenase, Coadministration with the antimetabolite 5-fluorouracil will require a substantial reduction in 5-fluorouracil dose to avoid toxici ty but may also improve the therapeutic index of 5-fluorouracil.