0090-9556/97/2507-0828-0839$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 7

Metabolism of the HIV-1 Reverse Transcriptase Inhibitor Delavirdine In Mice

Mayland Chang, Virendra K. Sood, Gracella J. Wilson, David A. Kloosterman, Phillip E. Sanders, Michael J. Hauer, Weirong Zhang, and Daniel G. Branstetter

Drug Metabolism Research (M.C., V.K.S., G.J.W., P.E.S., M.J.H.); Structural, Analytical and Medicinal Chemistry (D.A.K.); and Investigative Toxicology (W.Z., D.G.B.), Pharmacia & Upjohn, Inc.

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 metabolitearising from amide bond cleavagewas 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.