Preclinical metabolism of LB42908, a novel farnesyl transferase inhibitor, and its effects on the cytochrome P450 isozyme activities

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 9; pp. 3067 - 3071
• Main Authors: Chang, Minsun, Lee, Sung-Hak, Kim, Ho Jun, Koh, Jong-Sung, Kim, Aeri
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.05.2012; Elsevier
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; animal models; Animals; biochemical pathways; Biological and medical sciences; Biotransformation; cytochrome P-450; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme System - metabolism; dogs; drug interactions; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; General pharmacology; high performance liquid chromatography; Humans; Imidazoles - metabolism; Isoenzymes; isozymes; liver; liver microsomes; Medical sciences; metabolic studies; metabolites; metabolomics; Microsomes, Liver; Miscellaneous; monkeys; pharmacokinetics; Pharmacology. Drug treatments; Piperazines - metabolism; rats; toxicology; Preclinical hepatic metabolism; Unspecific monooxygenase; Enzyme; Isozyme; Transferases; Cytochrome P450; Liver; Glycosyltransferases; Protein farnesyltransferase; Preclinical trial; Metabolism; Biological activity; Farnesyl transferase inhibitor; Drug-metabolizing enzyme; Hexosyltransferases; Fucosylgalactose α-N-acetylgalactosaminyltransferase; Inhibitor; Drug interaction; Oxidoreductases; Pharmacokinetics; Chemical synthesis; Drug-drug interaction
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.03.070

Metabolism of LB42908, a novel farnesyl transferase inhibitor, was investigated for preclinical development. In vitro hepatic metabolism of LB42908 gave rise to at least 9 metabolites via phase I biotransformation pathways, which were characterized by HPLC-UV, LC-MS, and LC-MS/MS analyses. N-Dealkylation was shown to be a major phase I metabolic pathway. Species-specific in vitro metabolism of LB42908 was studied in liver fractions of rat, dog, monkey, and human. Order of metabolic stability is human≈dog>rat≈monkey in both S9 and microsomal fractions. Tissue-specific metabolism of LB42908 in various tissue homogenates of rats demonstrated that the liver was the major organ responsible for phase I metabolism of LB42908. The results from both qualitative and quantitative metabolism studies such as metabolic profiling and metabolic clearance indicated that dog would be the animal model of choice for preclinical toxicology studies. In addition, LB42908 was a potent CYP3A4 inhibitor in human liver microsomes and induced the activities of several CYP isozymes, implying that it has the potential for drug–drug interactions. Repeated dosing of LB42908 in rats did not significantly affect its own metabolism, indicating that long-term administration of LB42908 would not alter its pharmacokinetic profiles.