title: Desacetyl-diltiazem displays severalfold higher affinity to CYP2D6 compared with CYP3A4.
abstract: It has earlier been shown that the isoenzymes CYP2D6 and CYP3A4 are involved in O- and N-demethylation of diltiazem (DTZ), respectively. Apparently, CYP3A4 plays a more prominent role than CYP2D6 in the overall metabolism of DTZ. However, previous observations indicate that the opposite might be true for the pharmacologically active metabolite desacetyl-DTZ (M1). Thus, the aim of the present in vitro investigation was to study the relative affinity of M1 to CYP2D6 and CYP3A4. Immortalized human liver epithelial cells transfected with either CYP2D6 or CYP3A4 were used as a model system, and the presence of M1 and its metabolites in the cell culture medium was analyzed by high-performance liquid chromatography/UV detection both before and following 90 min of incubation. The estimated K(m) value for the CYP2D6-mediated O-demethylation of M1 was approximately 5 microM. In comparison, the affinity of M1 to CYP3A4 (N-demethylation) was about 100 times lower (K(m), approximately 540 microM) than to CYP2D6. These in vitro data suggest that M1 metabolism via CYP2D6, in contrast to the parent drug, probably is the preferred pathway in vivo. Metabolism mediated through CYP2D6 is associated with a substantial interindividual variability, and since M1 expresses pharmacological activity, individual CYP2D6 metabolic capacity might be an aspect to consider when using DTZ.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, N-0316 Oslo, Norway. espen.molden@farmasi.uio.no
authors.forename: Espen
authors.initials: E
authors.lastname: Molden
authors.forename: Anders
authors.initials: A
authors.lastname: Asberg
authors.forename: Hege
authors.initials: H
authors.lastname: Christensen
mesh_terms: D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000493:pharmacokinetics; D002478:Cells, Cultured; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; C037769:deacetyldiltiazem; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem