The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes.
1. The enzyme kinetics of dextromethorphan O-demethylation in liver microsomes from three extensive metabolisers (EM) with respect to CYP2D6 indicated high (Km1 2.2-9.4 microM) and low (Km2 55.5-307.3 microM) affinity sites whereas microsomes from two poor metabolisers (PM) indicated a single site (Km 560 and 157 microM). Similar differences were shown for 3-methoxymorphinan O-demethylation to 3-hydroxymorphinan (Km 6.9-9.6 microM in EM subjects; Km 307 and 213 microM in PM subjects). 2. Dextromethorphan O-demethylation was inhibited competitively by quinidine (Ki 0.1 microM), rac-perhexiline (Ki 0.4 microM), dextropropoxyphene (Ki 6 microM), rac-methadone (Ki 8 microM), and 3-methoxymorphinan (Ki 15 microM). These compounds were also potent inhibitors of 3-methoxymorphinan O-demethylation with IC50 values ranging from 0.02-12 microM. Anti-LKM1 serum inhibited both dextromethorphan and 3-methoxymorphinan O-demethylations in a titre-dependent manner. 3. The Michaelis-Menten constant for dextromethorphan N-demethylation to 3-methoxymorphinan (Km 632-977 microM) and dextrorphan N-demethylation to 3-hydroxymorphinan (Km 1571-4286 microM) did not differ between EM and PM microsomes. These N-demethylation reactions were not inhibited by quinidine and rac-methadone or LKM1 antibodies. 4. Dextromethorphan and 3-methoxymorphinan are metabolised by the same P450 isoform, CYP2D6, whereas the N-demethylation reactions are not carried out by CYP2D6.
Kerry
N L
NL
Department of Clinical and Experimental Pharmacology, University of Adelaide, Australia.
Somogyi
A A
AA
Bochner
F
F
Mikus
G
G
D001323:Autoantibodies / Q000276:immunology; D001667:Binding, Competitive; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011431:Dextropropoxyphene / Q000494:pharmacology; D003917:Dextrorphan / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008691:Methadone / Q000494:pharmacology; D008745:Methylation / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010480:Perhexiline / Q000494:pharmacology; D010641:Phenotype; D011802:Quinidine / Q000494:pharmacology
D001323:Autoantibodies; C060729:anti-liver kidney microsome antibody; D003917:Dextrorphan; C028657:3-methoxymorphinan; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; C054116:norlevorphanol; D011802:Quinidine; D010480:Perhexiline; D011431:Dextropropoxyphene; D008691:Methadone