The in vitro interaction of dexmedetomidine with human liver microsomal cytochrome P4502D6 (CYP2D6).

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 microM inhibited DEXTROase activity (IC50 = 1.8 +/- 0.25 microM; mean +/- SD; N = 5 livers) and was less potent than quinidine (QND), prototypical and clinically relevant CYP2D6 inhibitor (IC50 = 0.22 +/- 0.02 microM; mean Ki = 0.07 microM). Similar results were obtained with human B-lymphoblast microsomes containing cDNA-expressed CYP2D6 (DEX, IC50 = 2.2 microM; QND, IC50 0.15 microM). Formal kinetic analyses indicated that DEX was a reversible mixed (competitive/noncompetitive) inhibitor of DEXTROase activity in human liver microsomes, where Kies > Ki and alpha > 1 (Ki = 0.4 +/- 0.2 microM; Kies = 2.3 +/- 0.9 microM; alpha = 8.1 +/- 6.8; N = 3 livers). In addition, DEX elicited a Type IIb difference spectrum (lambda max approximately 436 nm; lambda min approximately 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 occurs via the 4(5)-substituted imidazole moiety. In this instance, binding was characterized by a spectral dissociation constant (Ks) of 0.4 microM that was identical to the Ki obtained with native human liver microsomes.