New selective inhibitors of cytochrome P4502B4 and an activator of cytochrome P450 3A6 in rabbit liver microsomes

We investigated interactions of adamantane, diamantane and their two substi tuted derivatives, 2-isopropenyl-2-methyladamantane (2-PMADA, 1) and 3 isop ropenyl-3-methyldiamantane (3-PMDIA, 2), with various isoforms of rabbit cy tochrome P450 (CYP). The data of spectroscopic experiments showed that all the substances are bound to the substrate binding site of rabbit CYP2B4 and CYP3A6. 1 and 2 are compounds having higher affinities to these CYP isofor ms than adamantane and diamantane. All compounds inhibit CYP2B4 specific en zyme activity (the 7-pentoxyresorufin O-depentylase activity). The 50% inhi bition of CYP2B4 was due to 3.82, 0.61, 0.66 and 0.37 mu M adamantane, diam antane, 1 and 2, respectively. The products formed during the CYP2B4-mediat ed metabolism of studied substances are less effective inhibitors than pare nt compounds. An opposite effect of 1 on CYP3A6 was determined. The specifi c enzyme activity of CYP3A6 increased to 138% of control when 1 was used in the presence of 40 mu M erythromycin as a substrate. Here, we report the f inding of a new activator of CYP3A6 having the structure quite different fr om that of CYP3A6 activators known to date.