Involvement of CYP2D1 in the metabolism of carteolol by male rat liver microsomes

Abstract

1. The metabolism of carteolol, a β-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-Mente n kinetics with a K_m = 11.0 ± 5.4 μM and a V_max = 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 MichaelisMenten kinetics. 3. The cytochrome P450 isoforms involved in 8-hydroxylation of carteolol were investigated using selective chemical inhibitors and polyclonal anti-P450 antibodies. Quinine (K_i = 0.06 μM) and quinidine (K_i = 2.0 μM), 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-hydroxycarteolo l 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 β-adrenoceptor blocking drugs.