Dimemorfan N-demethylation by mouse liver microsomal cytochrome P450 enzymes.
Dimemorfan (d-3-methyl-N-methylmorphinan), an analogue of dextromethorphan, is commonly used as a non-opioid antitussive. To clarify the contribution of cytochrome P450 (P450) in dimemorfan N-demethylation, effects of selective inducers and inhibitors were studied in ICR mice. Phenobarbital (PB)- and dexamethasone (Dex)-treatments caused 5-fold increases of liver microsomal dimemorfan N-demethylation activity. In untreated mouse liver microsomes, demethylation activity was strongly inhibited by a CYP3A inhibitor, ketoconazole. In PB-and Dex-treated mouse liver microsomes, ketoconazole caused strong inhibition, whereas orphenadrine caused a decrease of less than 20%. Pretreatment of control mouse liver microsomes with anti-CYP3A inhibited demethylation activity, whereas pre-treatment with anti-CYP2B had no effect. In PB-and Dex-treated mouse liver microsomes, the demethylation activity was inhibited by both anti-CYP3A and anti-CYP2B. In control mice, the intrinsic clearance of dimemorfan from N-demethylation was 5.8 microl min(-1)mg protein(-1). In PB- and Dex-treated mice, the correlation coefficient of fitting using one-enzyme and two-enzyme models were similar. The intrinsic clearances of induced mouse liver microsomes were similar. These results revealed that CYP3A played a major role in hepatic demethylation in untreated mice. Both CYP3A and CYP2B were involved in this demethylation in PB- and Dex-treated mice.
Chou
Yueh-Ching
YC
Department of Pharmacy, Department of Internal Medicine, Taipei Veteran General Hospital, Taipei 112, Taiwan, R.O.C.
Ueng
Yune-Fang
YF
Chou
Chia-Yu
CY
Tien
Jung-Hsiung
JH
D000818:Animals; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D016014:Linear Models; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000201:enzymology*; D009019:Morphinans / Q000737:chemistry / Q000378:metabolism*; D009966:Orphenadrine / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D008565:Membrane Proteins
D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003907:Dexamethasone; D007654:Ketoconazole; D009019:Morphinans; D009966:Orphenadrine; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital; C012621:dimemorfan; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins