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 administration of [14C]
delavirdine mesylate at single doses of 10 and/or 250 mg/kg and multiple doses of 200 mg/kg/day. Studies were conducted with 14C-carboxamide and 2-14C-pyridine labels, as well as 13C3-labeled
drug to facilitate metabolite identification. Excretion was dose dependent with 57-70% of the radioactivity eliminated in feces and 25-36% in urine. Pharmacokinetic analyses of
delavirdine and its N-desisopropyl metabolite (desalkyl
delavirdine) in plasma showed that
delavirdine was absorbed and metabolized rapidly, that it constituted a minor component in circulation, that its pharmacokinetics were nonlinear, and that its metabolism to desalkyl
delavirdine was capacity limited or inhibitable.
Delavirdine did not significantly cross the blood-brain barrier; however, its N-isopropylpyridinepiperazine metabolite arising from
amide bond cleavage-was present in brain at levels 2- to 3-fold higher than in plasma. The metabolism of
delavirdine in the mouse was extensive and involved
amide bond cleavage, N-desalkylation, hydroxylation at the C-6' position of the
pyridine ring, and
pyridine ring-cleavage as determined by MS and/or 1H and 13C NMR spectroscopies. N-desalkylation and
amide bond cleavage were the primary metabolic pathways 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 multiple doses.