An in vitro evaluation of the victim and perpetrator potential of the anticancer agent laromustine (VNP40101M), based on reaction phenotyping and inhibition and induction of cytochrome P450 enzymes.
Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. Laromustine generates two types of reactive intermediates: 90CE and methylisocyanate. When incubated with rat, dog, monkey, and human liver microsomes, [(14)C]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 involved in C-7 formation) as well as of CYP2C19. K(i) values were 125 microM for CYP2B6, 297 muM for CYP3A4/5, and 349 microM for CYP2C19 and were greater than the average clinical plasma C(max) of laromustine (25 microM). There was evidence of time-dependent inhibition of CYP1A2, CYP2B6, and CYP3A4/5. Treatment of primary cultures of human hepatocytes with up to 100 microM 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 the laromustine has 1) negligible victim potential with respect to metabolism by cytochrome P450 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 after the duration of intravenous administration of this anticancer drug, but the clinical effects of such interactions are likely to be insignificant.
Nassar
Alaa-Eldin F
AE
Vion Pharmaceuticals, Inc., Four Science Park, New Haven, CT 06511, USA. nassaral@aol.com
King
Ivan
I
Paris
Brandy L
BL
Haupt
Lois
L
Ndikum-Moffor
Florence
F
Campbell
Rebecca
R
Usuki
Etsuko
E
Skibbe
Jennifer
J
Brobst
Dan
D
Ogilvie
Brian W
BW
Parkinson
Andrew
A
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004285:Dogs; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D000882:Haplorhini; D006801:Humans; D006834:Hydrazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D006834:Hydrazines; D007527:Isoenzymes; D013449:Sulfonamides; C483604:laromustine; D009249:NADP; D003577:Cytochrome P-450 Enzyme System