Br J Cancer. 1998 Nov;78(9):1170-4.  

Potent and non-specific inhibition of cytochrome P450 by JM216, a new oral
platinum agent.

Ando Y, Shimizu T, Nakamura K, Mushiroda T, Nakagawa T, Kodama T, Kamataki T.

Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido
University, Sapporo, Japan.

Bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV), JM216, is the first
antineoplastic platinum compound that can be given to patients orally. Several
phase II clinical trials of JM216 monotherapy have already been reported.
However, no information on the potential drug interactions caused by JM216 is
available. In this study, the capacity of JM216 to inhibit cytochrome P450 (CYP)
in human liver microsomes was investigated by measuring the inhibition potential
(IC50 and Ki) on prototype reactions. Specific substrates of CYP included
testosterone (catalysed by CYP3A4), paclitaxel (CYP2C8), 7-ethoxyresorufin
(CYP1A1, CYP1A2), coumarin (CYP2A6), aniline (CYP2E1) and (+/-)-bufuralol
(CYP2D6). JM216 inhibited the catalytic activities of CYP isozymes. The IC50
values were between 0.3 microM and 10 microM, indicating strong and non-specific
inhibitory effects of JM216. The inhibition occurred in a non-competitive
manner, and the Ki value was 1.0 and 0.9 microM for metabolite formation of
testosterone and paclitaxel respectively. Therefore, some in vivo studies should
be conducted to determine whether or not there is a correlation between in vivo
and in vitro results.

PMID: 9820175 [PubMed - indexed for MEDLINE]