caa a22 4500 475818709 CHVBK 20180406123816.0 cr unu---uuuuu 170329e20001101xx s 000 0 eng 10.1007/s002280000182 doi (NATIONALLICENCE)springer-10.1007/s002280000182 CYP2D6 is involved in O -demethylation of diltiazem [Elektronische Daten] An in vitro study with transfected human liver cells [Espen Molden, Anders Åsberg, Hege Christensen] Abstract.: Objective: In a previous study of diltiazem (DTZ) pharmacokinetics in renal transplant patients, we speculated that a polymorphic enzyme could be involved in O-demethylation of diltiazem. The aim of this in vitro study was to investigate whether O-demethylation of DTZ is mediated by cytochrome P 450-2D6 (CYP2D6). Methods: DTZ was incubated with transfected human liver epithelial (THLE) cells expressing CYP2D6 (T5-2D6 clone). Metabolism of DTZ was studied over a concentration range of 12.5-400µM and in the presence of quinidine (a CYP2D6 inhibitor) or erythromycin (a CYP3A4 inhibitor). THLE cells lacking CYP2D6 activity (T5-neo clone) were used as control. The culture medium of the cells, in which DTZ was dissolved, was analysed for DTZ and metabolites prior to and after 8h of incubation using high-performance liquid chromatography (HPLC, UV detection). Authentic O-demethyl-DTZ (Mx) was not available, and this metabolite was therefore not identifiable. Results: Desacetyl-O-demethyl-DTZ (M4) was exclusively produced during incubations of DTZ with THLE cells expressing CYP2D6. The rate of M4 formation was described using Michaelis Menten kinetics in the concentration range of DTZ used. Production of M4 was inhibited by quinidine, but not erythromycin. An unidentified chromatographic peak, which was interpreted to be Mx, showed the same pattern of formation as M4 both in absence and presence of inhibitors. N-demethylated metabolites, formed by CYP3A4, were not observed in any of the cell lines. Conclusion: Evidence was provided in vitro that O-demethylation of DTZ is mediated by the polymorphic isoenzyme CYP2D6. Involvement of CYP2D6 in the metabolism of DTZ may have clinical implications regarding pharmacokinetic variability and interactions. Springer-Verlag, 2000 Diltiazem Metabolism CYP2D6 nationallicence Molden Espen Department of Pharmacology, School of Pharmacy, University of Oslo, Oslo, Norway aut Åsberg Anders Laboratory for Renal Physiology, Section of Nephrology, Medical Department, The National Hospital, Oslo, Norway aut Christensen Hege Department of Pharmacology, School of Pharmacy, University of Oslo, Oslo, Norway aut European Journal of Clinical Pharmacology Springer-Verlag 56/8(2000-11-01), 575-579 0031-6970 56:8<575 2000 56 228 https://doi.org/10.1007/s002280000182 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280000182 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Molden Espen Department of Pharmacology, School of Pharmacy, University of Oslo, Oslo, Norway aut NATIONALLICENCE 700 1- Åsberg Anders Laboratory for Renal Physiology, Section of Nephrology, Medical Department, The National Hospital, Oslo, Norway aut NATIONALLICENCE 700 1- Christensen Hege Department of Pharmacology, School of Pharmacy, University of Oslo, Oslo, Norway aut NATIONALLICENCE 773 0- European Journal of Clinical Pharmacology Springer-Verlag 56/8(2000-11-01), 575-579 0031-6970 56:8<575 2000 56 228 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer