Received for publication October 17, 2005.
Revised January 24, 2006.
Accepted for publication January 25, 2006.

IDENTIFICATION OF HUMAN LIVER CYTOCHROME P450 ENZYMES RESPONSIBLE FOR THE METABOLISM OF LONAFARNIB (Sarasar^TM)

Abstract

Lonafarnib (Sarasar^TM), a farnesyl transferase inhibitor, is currently under development for the treatment of solid tumors. Incubation of lonafarnib with human liver microsomes resulted in the formation of four oxidative metabolites (M1, M2, M3, and M4). Minor to trace levels of these metabolites were detected in humans following multiple dose administration of lonafarnib. LC-MS analyses exhibited a mass to charge ratio (m/z) for the (M+H)⁺ ion of M1, M2, M3, and M4 at 653, 635, 669, and 653 Th, respectively. These metabolites respectively resulted from changes of +O, -2H, +2O, and +O relative to lonafarnib. Recombinant human CYP3A4 and CYP3A5 exhibited catalytic activity with respect to the formation of M1, M2 and M3, while CYP2C8 exhibited catalytic activity with respect to the formation of M4. There was a high correlation between the formation of M1, determined in 10 human liver microsomal samples and 6-hydroxylation of testosterone catalyzed by CYP3A4/5 (r=0.93). The IC₅₀ values of ketoconazole for inhibition of M1 and M2 were 0.61 and 0.92 µM, respectively. The formation of M4 by human liver microsomes was inhibited 72% by 50 µM quercetin suggesting that the formation of M4 was mediated via CYP2C8. A CYP3A4/5-specific inhibitory monoclonal antibody inhibited the formation of M1, M2 and M3 by 85%, 75% and 100% respectively. In conclusion, the formation of metabolites M1, M2 and M3 from lonafarnib was mediated via CYP3A4 and CYP3A5.

Key words: CYP inhibition, CYP3A, cytochrome P450, cytochrome P450 catalyzed oxidations, drug disposition, enzyme kinetics, human CYP enzymes

This article has been cited by other articles:

				M. W. Kieran, R. J. Packer, A. Onar, S. M. Blaney, P. Phillips, I. F. Pollack, J. R. Geyer, S. Gururangan, A. Banerjee, S. Goldman, et al. Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study J. Clin. Oncol., July 20, 2007; 25(21): 3137 - 3143. [Abstract] [Full Text] [PDF]

				N. E. Ready, A. Lipton, Y. Zhu, P. Statkevich, E. Frank, D. Curtis, and R. M. Bukowski Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Weekly Paclitaxel in Patients with Solid Tumors Clin. Cancer Res., January 15, 2007; 13(2): 576 - 583. [Abstract] [Full Text] [PDF]