title: Involvement of CYP2D1 in the metabolism of carteolol by male rat liver microsomes.
abstract: 1. The metabolism of carteolol, a beta-adrenoceptor blocking drug, was investigated in male Sprague-Dawley rat liver microsomes. 2. The formation of 8-hydroxycarteolol was the principal metabolic pathway of carteolol in vitro and followed Michaelis-Menten kinetics with a K(m) = 11.0 +/- 5.4 microM and a Vmax = 1.58 +/- 0.64 nmol/min/nmol P450 respectively (mean +/- SD, n = 5). Eadie-Hofstee plot analysis of carteolol 8-hydroxylase activity confirmed single-enzyme Michaelis-Menten kinetics. 3. The cytochrome P450 isoforms involved in 8-hydroxylation of carteolol were investigated using selective chemical inhibitors and polyclonal anti-P450 antibodies. Quinine (Ki = 0.06 microM) and quinidine (Ki = 2.0 microM), selective inhibitors of CYP2D1, competitively inhibited 8-hydroxycarteolol formation. Furthermore, only anti-human CYP2D6 antibody inhibited this reaction. 4. These results suggest that carteolol is metabolized to 8-hydroxycarteolol by CYP2D1. The K(m) of carteolol for CYP2D1 in male rat liver microsomes was much greater than those of propranolol or bunitrolol, indicating that carteolol has a lower affinity for CYP2D1 compared with these other beta-adrenoceptor blocking drugs.
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Umehara
authors.forename: S
authors.initials: S
authors.lastname: Kudo
authors.forename: M
authors.initials: M
authors.lastname: Odomi
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002354:Carteolol / Q000031:analogs & derivatives / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009249:NADP / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000319:Adrenergic beta-Antagonists; D000906:Antibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D009249:NADP; C060345:8-hydroxycarteolol; D002354:Carteolol; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine