J Pharmacol Exp Ther. 1995 Dec;275(3):1527-34.  

Potent and selective inactivation of human liver microsomal cytochrome P-450
isoforms by L-754,394, an investigational human immune deficiency virus protease
inhibitor.

Chiba M, Nishime JA, Lin JH.

Department of Drug Metabolism, Merck Research Laboratories, West Point,
Pennsylvania, USA.

L-754,394, N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-(1,1-dimethylethylaminocarbonyl
)-4- [(furo[2,3-b]pyridin-5-yl)methyl]piperazin-1-yl]-4(S)-hydroxy-2(R) -
phenylmethylpentanamide, is a potent and specific inhibitor of the human immune
deficiency virus (HIV) protease. The drug selectively inhibited human liver
microsomal CYP 3A4-dependent testosterone 6 beta-hydroxylase and CYP
2D6-dependent bufuralol 1'-hydroxylase activities in a time- and
concentration-dependent manner in the presence of an NADPH-generating system.
L-754,394 was found to be a very potent inactivator of CYP 3A4. Thus, for
testosterone 6 beta-hydroxylase, the inactivation kinetic constants, Kl and
kinact, were 7.5 microM and 1.62 min-1, respectively, and the partition ratio
(moles product formed per moles enzyme inactivated) was approximately 1.35. To a
lesser extent, L-754,394 also was an inactivator of CYP 2D6, for which the
corresponding values for Kl, kinact and partition ratio were 32 microM, 0.18
min-1 and 40, respectively. CYP 3A4 inactivation was reduced markedly by
ketoconazole, a selective CYP 3A4 inhibitor. Similarly, CYP 2D6 inactivation
also was prevented by quinidine, a specific competitive inhibitor of this
isoform. However, exogenously added nucleophiles (GSH, semicarbazide and
N-acetylcysteine) failed to protect against P-450 inactivation. These results
suggest that the inactivation process likely is mediated by a reactive
metabolite of L-754,394 that alkylates, and thereby destroys, the enzyme.
Furthermore, this electrophilic intermediate may not be released into the medium
before the inactivation event.

PMID: 8531125 [PubMed - indexed for MEDLINE]