Abstract
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.
Highlights
JM216 inhibited the catalytic activities of cytochrome P450 (CYP) isozymes
The IC5. values were between 0.3 1M and 1O 1M, indicating strong and non-specific inhibitory effects of JM216
The inhibition occurred in a non-competitive manner, and the K value was 1.0 and 0.9 gm for metabolite formation of testosterone and paclitaxel respectivety
Summary
JM2 16 was kindly provided by Bristol-Myers Squibb JM216 (200 l-m) and cisplatin (100 ILm) were suspended in water and stored at 4CC in the dark. The stability of JM2 16 in water at this concentration was tested. 98.8%c of the drug remained unchanred after 48 h in the dark. 95.5% after 2 h under room light (Bristol-Myers Squibb proprietarv information). Glucose 6-phosphate and glucose 6-phosphate dehvdrogrenase were obtained from Oriental Yeast 7-hvdroxvcoumarin and aniline hvdrochlonrde were from Wako Pure Chemical Industries Japan): 11 B- and 6,hydroxvtestosterones from Steraloid USA): paminophenol hydrochloride from Tokyo Chemical Industries Japan): and (±)-bufuralol hydrochloride and l'-hydroxx bufuralol from Gentest All other chemicals were of the hirhest grade commercially available
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