title: TRAM-34, a putatively selective blocker of intermediate-conductance, calcium-activated potassium channels, inhibits cytochrome P450 activity.
abstract: TRAM-34, a clotrimazole analog characterized as a potent and selective inhibitor of intermediate-conductance, calcium-activated K(+) (IKCa) channels, has been used extensively in vitro and in vivo to study the biological roles of these channels. The major advantage of TRAM-34 over clotrimazole is the reported lack of inhibition of the former drug on cytochrome P450 (CYP) activity. CYPs, a large family of heme-containing oxidases, play essential roles in endogenous signaling and metabolic pathways, as well as in xenobiotic metabolism. However, previously published work has only characterized the effects of TRAM-34 on a single CYP isoform. To test the hypothesis that TRAM-34 may inhibit some CYP isoforms, the effects of this compound were presently studied on the activities of four rat and five human CYP isoforms. TRAM-34 inhibited recombinant rat CYP2B1, CYP2C6 and CYP2C11 and human CYP2B6, CYP2C19 and CYP3A4 with IC50 values ranging from 0.9 µM to 12.6 µM, but had no inhibitory effects (up to 80 µM) on recombinant rat CYP1A2, human CYP1A2, or human CYP19A1. TRAM-34 also had both stimulatory and inhibitory effects on human CYP3A4 activity, depending on the substrate used. These results show that low micromolar concentrations of TRAM-34 can inhibit several rat and human CYP isoforms, and suggest caution in the use of high concentrations of this drug as a selective IKCa channel blocker. In addition, in vivo use of TRAM-34 could lead to CYP-related drug-drug interactions.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, United States of America.
authors.forename: Jay J
authors.initials: JJ
authors.lastname: Agarwal
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhang
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Mongin
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Hough
mesh_terms: D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D007527:Isoenzymes; D026902:Potassium Channel Blockers; D011720:Pyrazoles; C411671:TRAM 34