Inhibition of Major Cytochrome P450 Enzyme Activities in Human Liver Microsomes by 9‐a and WES‐1, two Novel Carbonic Anhydrase Inhibitors.

Abstract

Both 9‐a (sulphonamide derivative) and WES‐1 (coumarin derivative) were designed and synthesized as potential selective Carbonic Anhydrase Inhibitors, and are currently being tested for anti‐cancer activity. This study was undertaken to investigate their potential inhibitory effects on the major Cytochrome P450 (CYP) drug metabolizing enzymes in human liver microsomes using specific CYP probe substrates and liquid chromatography‐tandem mass spectrometry. 9a potently inhibited CYP2E1‐catalyzed chlorzoxazone‐6′‐hydrolylation and CYP2C9‐catalyzed tolbutamide‐4′‐hydrolylation with IC50 values of 0.05 and 0.7 μM, respectively. CYP2A6‐catalyzed coumarin‐7′‐hydroxylation and CYP3A4‐catalyzed testosterone‐6β‐hydroxylation were moderately inhibited by 9‐a with IC50 values of 2.7 and 12 μM, respectively. The rest of the tested CYP enzymes were weakly or negligibly inhibited by 9‐a. WES‐1, on the other hand, demonstrated weak inhibitory effects on CYP2C19‐mediated [S]‐mephenytoin‐4′‐hydrolylation, CYP2C9 activity, and CYP2D6‐catalyzed Dextromethorphan dealkylation with IC50 values of 39, 42.5, and 57.5 μM, respectively. This in‐vitro data indicates that more in vivo studies should be conducted to examine the potential pharmacokinetic drug‐drug interactions with 9‐a due to its potent and moderate inhibition of CYP2A6, CYP2C9, CYP2E1, and CYP3A4.Inhibitory effect of WES‐1 on the major CYP enzymes in human liver microsomesFigure 1Inhibitory effect of 9a on the major CYP enzymes in human liver microsomesFigure 2