TY - JOUR T1 - The <em>In Vitro</em> Interaction of Dexmedetomidine with Human Liver Microsomal Cytochrome P4502D6 (CYP2D6) JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 651 LP - 655 VL - 25 IS - 5 AU - A. David Rodrigues AU - Ellen M. Roberts Y1 - 1997/05/01 UR - http://dmd.aspetjournals.org/content/25/5/651.abstract N2 - The effect of dexmedetomidine (DEX) on cytochrome P4502D6 (CYP2D6)-dependent dextromethorphan O-demethylase (DEXTROase) activity was studied using native human liver microsomes. DEX (0.01–4.0 μM) inhibited DEXTROase activity (IC50 = 1.8 ± 0.25 μM; mean ± SD; N = 5 livers) and was less potent than quinidine (QND), a prototypical and clinically relevant CYP2D6 inhibitor (IC50 = 0.22 ± 0.02 μM; mean Ki = 0.07 μM). Similar results were obtained with human B-lymphoblast microsomes containing cDNA-expressed CYP2D6 (DEX, IC50 = 2.2 μM; QND, IC50 = 0.15 μM). Formal kinetic analyses indicated that DEX was a reversible mixed (competitive/noncompetitive) inhibitor of DEXTROase activity in human liver microsomes, where Kies &gt;Ki and α &gt; 1 (Ki = 0.4 ± 0.2 μM; Kies = 2.3 ± 0.9 μM; α = 8.1 ± 6.8; N = 3 livers). In addition, DEX elicited a Type llb difference spectrum (λmax ∼436 nm; λmin ∼414 nm) when added to cDNA-expressed CYP2D6 under aerobic (oxidized) conditions. These data indicated that DEX was able to bind reversibly to the heme (ferric) iron of CYP2D6. It is postulated that binding occursvia the 4(5)-substituted imidazole moiety. In this instance, binding was characterized by a spectral dissociation constant (Ks ) of 0.4 μM that was identical to theKi obtained with native human liver microsomes. The American Society for Pharmacology and Experimental Therapeutics ER -