Assessment of the involvement of CYP3A in the vitro metabolism of a new modulator of MDR in cancer chemotherapy, OC144-193, by human liver microsomes

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 26; no. 4; pp. 273 - 282
• Main Authors: GUNS, Emma S, BULLOCK, Peter L, REIMER, Mark L. J, DIXON, Ross, BALLY, Marcel, MAYER, Lawrence D
• Format: Journal Article
• Language: English
• Published: Genève Médecine et hygiène 01.10.2001
• Subjects: Antineoplastic agents; Aryl Hydrocarbon Hydroxylases; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Chromatography, High Pressure Liquid; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Drug Resistance, Multiple; Humans; Imidazoles - metabolism; Imidazoles - pharmacokinetics; In Vitro Techniques; Medical sciences; Microsomes, Liver - metabolism; Models, Chemical; Oxidoreductases, N-Demethylating - metabolism; Pharmacology. Drug treatments; Antineoplastic agent; Human; Imidazole derivatives; Drug combination; Unspecific monooxygenase; Enzyme; Digestive system; Isozyme; Cytochrome P450; Liver; P Glycoprotein; Adjuvant treatment; Microsome; Metabolism; In vitro; Multiple resistance; Drug-metabolizing enzyme; Drug interaction; Oxidoreductases
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/bf03226382

The novel substituted imidazole compound, OC144-093 exhibits potent biological activity in vitro and in vivo for reversal of P-glycoprotein (PgP) based resistance to cancer chemotherapy. Its mechanism of action relies upon its inhibitory interaction with the mdr1 gene product, a known mediator of multidrug resistance (MDR). Overlapping substrate specificities and tissue distribution of cytochrome P450 3A (CYP3A) and PgP indicate the potential for drug-drug interactions when modulator and anticancer agent are co-administered. We have examined the metabolism of OC144-093 in vitro using human liver microsomes to determine if CYP3A is involved. Our results show that OC144-093 is converted to one major metabolite (M1) in human liver microsomes which was identified by LCMS to be the O-deethylated derivative. Km and Vmax for O-deethylation were determined as 3.96+/-0.67 microM and 32.08+/-9.73 pmol/mg protein/min, respectively (n=3). Correlation studies conducted in a panel of human livers phenotyped for specific P450 enzyme activity showed a significant relationship between M1 formation and the activity of CYP2C9, CYP2B6, CYP2E1 and CYP3A4. Treatment of microsomes with carbon monoxide gas inhibited M1 formation and diethyldithiocarbamate and ketoconazole (>3 microM), non-specific CYP inhibitors, gave IC50 values of 124.4+/-21.6 microM and 25.3+/-3.2 microM respectively for the inhibition of O-deethylation, also implicating the involvement of CYP enzymes. Specific CYP inhibitors of CYP3A4 were essentially non-inhibitory to M1 formation. We can conclude therefore that OC144-093 is not extensively metabolised in human liver microsomes although conversion to its O-deethylated derivative does occur. Our data indicates that this conversion is not mediated by CYP3A4.