THE IN-VITRO INTERACTION OF DEXMEDETOMIDINE WITH HUMAN LIVER MICROSOMAL CYTOCHROME P4502D6 (CYP2D6)

The effect of dexmedetomidine (DEX) on cytochrome P4502D6 (CYP2D6)-dep endent dextromethorphan O-demethylase (DEXTROase) activity was studied using native human liver microsomes. DEX (0.01-4.0 mu M) inhibited DE XTROase activity (IC50 = 1.8 +/- 0.25 mu M; mean +/- SD; N = 5 livers) and was less potent than quinidine (QND), a prototypical and clinical ly relevant CYP2D6 inhibitor (IC50 = 0.22 +/- 0.02 mu M; mean K-i = 0. 07 mu M). Similar results were obtained with human B-lymphoblast micro somes containing cDNA-expressed CYP2D6 (DEX, IC50 = 2.2 mu M; QND, IC5 0 = 0.15 mu M). Formal kinetic analyses indicated that DEX was a rever sible mixed (competitive/noncompetitive) inhibitor of DEXTROase activi ty in human liver microsomes, where K-ies > K-i and alpha > 1 (K-i = 0 .4 +/- 0.2 mu M; K-ies = 2.3 +/- 0.9 mu M; alpha = 8.1 +/- 6.8; N = 3 livers). In addition, DEX elicited a Type IIb difference spectrum (lam bda(max) similar to 436 nm; lambda(min) similar to 414 nm) when added to cDNA-expressed CYP2D6 under aerobic (oxidized) conditions. These da ta 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)-sub stituted imidazole moiety. In this instance, binding was characterized by a spectral dissociation constant (K-s) of 0.4 mu M that was identi cal to the K-i obtained with native human liver microsomes.