Received for publication March 11, 2009.
Revised June 1, 2009.
Accepted for publication June 8, 2009.

An in vitro evaluation of the victim and perpetrator potential of the anti-cancer agent laromustine (VNP40101M), based on reaction phenotyping and inhibition and induction of cytochrome P450 (CYP) enzymes

Abstract

Laromustine (VNP40101M; a.k.a. Cloretazine) is a novel sulfonylhydrazine alkylating (anti-cancer) agent. Laromustine generates two types of reactive intermediates: 90CE and methylisocyanate. When incubated with rat, dog, monkey and human liver microsomes, [¹⁴C]-laromustine was converted to 90CE (C-8) and seven other radioactive components (C-1 - C-7). There was little difference in the metabolite profile among the species examined, in part because the formation of most components (C-1 - C-6 and 90CE) did not require NADPH, but involved decomposition and/or hydrolysis. The exception was C 7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Laromustine caused direct inhibition of CYP2B6 and CYP3A4/5 (the two enzymes in¬volv¬ed in C-7 formation) as well as CYP2C19. K_i values were 125 µM for CYP2B6, 297 µM for CYP3A4/5, and 349 µM for CYP2C19, and were greater than the average clinical plasma Cmax of laromustine (25 µM). There was evidence of time-dependent inhibition of CYP1A2, CYP2B6 and CYP3A4/5. Treatment of primary cultures of human hepatocytes with up to 100 µM laromustine did not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4/5, but the highest concentration of laromustine decreased the activity and levels of immunoreactive CYP3A4. The results of this study suggest laromustine has (1) negligible victim potential with respect to metabolism by CYP enzymes, (2) negligible enzyme-inducing potential, and (3) the potential in some cases to cause inhibition of CYP2B6, CYP3A4 and possibly CYP2C19 during and shortly following the duration of intravenous administration of this anticancer drug, but the clinical effects of such interactions are likely to be insignificant.

Key words: CYP induction, CYP inhibition, drug-drug interactions, human CYP enzymes