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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.

Abstract：

: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.

journal_name

Eur J Drug Metab Pharmacokinet

journal_title

European journal of drug metabolism and pharmacokinetics

authors

Guns ES,Bullock PL,Reimer ML,Dixon R,Bally M,Mayer LD

doi

10.1007/BF03226382

keywords:

subject

Has Abstract

pub_date

2001-10-01 00:00:00

pages

273-82

issue

eissn

0378-7966

issn

2107-0180

journal_volume

pub_type

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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.