METABOLISM OF THE HIV-1 REVERSE-TRANSCRIPTASE INHIBITOR DELAVIRDINE IN MICE

Delavirdine mesylate (U-90152T) is a highly specific nonnucleoside HIV -1 reverse transcriptase inhibitor currently under development for the treatment of AIDS. The excretion, disposition, brain penetration, and metabolism of delavirdine were investigated in CD-1 mice after oral a dministration of [C-14]delavirdine mesylate at single doses of 10 and/ or 250 mg/kg and multiple doses of 200 mg/kg/day. Studies were conduct ed with C-14-carboxamide and 2-C-14-pyridine labels, as well as C-13(3 )-labeled drug to facilitate metabolite identification. Excretion was dose dependent with 57-70% of the radioactivity eliminated in feces an d 25-36% in urine. Pharmacokinetic analyses of delavirdine and its N-d esisopropyl metabolite (desalkyl delavirdine) in plasma showed that de lavirdine was absorbed and metabolized rapidly, that it constituted a minor component in circulation, that its pharmacokinetics were nonline ar, and that its metabolism to desalkyl delavirdine was capacity limit ed or inhibitable. Delavirdine did not significantly cross the blood-b rain barrier; however, its N-isopropylpyridinepiperazine metabolite--a rising from amide bond cleavage--was present in brain at levels 2- to 3-fold higher than in plasma. The metabolism of delavirdine in the mou se was extensive and involved amide bond cleavage, N-desalkylation, hy droxylation at the C-6' position of the pyridine ring, and pyridine ri ng-cleavage as determined by MS and/or H-1 and C-13 NMR spectroscopies . N-desalkylation and amide bond cleavage were the primary metabolic p athways at low drug doses and, as the biotransformation of delavirdine to desalkyl delavirdine reached saturation or inhibition, amide bond cleavage became the predominant pathway at higher doses and after mult iple doses.