Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar).

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Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S

Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar).

Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27.

PubMed ID

16443667 [ View in PubMed

]

Abstract

Lonafarnib (Sarasar), 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 after multiple-dose administration of lonafarnib. Liquid chromatography-mass spectrometry 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, whereas 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 6beta-hydroxylation of testosterone catalyzed by CYP3A4/5 (r = 0.93). The IC(50) values of ketoconazole for inhibition of M1 and M2 were 0.61 and 0.92 microM, respectively. The formation of M4 by human liver microsomes was inhibited 72% by 50 microM 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.

DrugBank Data that Cites this Article

Drugs

Lonafarnib

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Lonafarnib	Cytochrome P450 2C8	Protein	Humans	No	Substrate Inhibitor	Details
Lonafarnib	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details
Lonafarnib	Cytochrome P450 3A5	Protein	Humans	No	Substrate Inhibitor	Details

Drug Reactions

Reaction
Lonafarnib DB06448 Lonafarnib metabolite M1 DBMET03217	Details