DP7, a novel dihydropyridine multidrug resistance reverter, shows only weak inhibitory activity on human CYP3A enzyme(s).
The aim of this study was to investigate the effects of 3,5-dibenzoyl-4-(3-phenoxy-phenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7), a novel multidrug resistance (MDR) reverter, on cytochrome P450 (CYP)-activities by human and rat liver microsomes. Effects of DP7 were assessed with use of selective substrates, markers of CYP activities. With rat microsomes, ethoxyresorufin (ETR) was used as substrate for CYP1A1, penthoxyresorufin (PTR) for 2B, benzyloxyresorufin (BZR) for 1A1/2, 2B, 2C, 3A. CYP3A enzyme activities of rat (3A2) and human (3A4) liver microsomes, were assessed fluorimetrically using either 7-benzyloxy-quinoline (BQ) or [3-[3(3,4-difluorobenzyl)oxy]-5,5-dimethyl-4-[4-(methylsulfonyl)-phenyl]furan-2-(5H)-one] (DFB). When rat microsomes were incubated with DP7, concentration-inhibition curves were obtained. DP7 inhibitions gave IC(50) values of 3.8 microM for PTR, 3.8 microM for ETR and 10.4 microM for BZR and were not competitive in nature; moreover, they were reversible. When BQ was used as substrate of rat microsomes, DP7 inhibited its oxidation with an IC(50) value of 4.17 microM, while this oxidation was inhibited by only 25% at the highest DP7 concentration used (75 microM) with human microsomes. On the contrary, when DFB was used as substrate, DP7 showed identical IC(50) values (34.67 microM) with microsomal preparations from either species. The moderate inhibition of CYP isoforms of rat liver microsomes and the weak inhibition of human CYP3A4 enzyme activity operated by DP7, suggest that DP7 in man should not give rise to important, unpredictable pharmacokinetic interactions. This conclusion supports the role of this compound as a lead for the development of novel MDR reverterting dihydropyridines of therapeutic interest.
D'Elia
Paolo
P
Department of Neurosciences, University of Siena, Siena, Italy.
De Matteis
Francesco
F
Dragoni
Stefania
S
Shah
Anamik
A
Sgaragli
Giampietro
G
Valoti
Massimo
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
C492000:3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine; D018435:ATP Binding Cassette Transporter, Subfamily B; D065692:Cytochrome P-450 CYP3A Inhibitors; D004095:Dihydropyridines; D007527:Isoenzymes; D051544:Cytochrome P-450 CYP3A