Comparative study of the oxidation of propranolol enantiomers in hepatic and small intestinal microsomes from cynomolgus and marmoset monkeys.
Oxidative metabolism of propranolol (PL) enantiomers (R-PL and S-PL) to 4-hydroxypropranolol (4-OH-PL), 5-OH-PL and N-deisopropylpropranolol (NDP) was examined in hepatic microsomes from cynomolgus and marmoset monkeys and in small intestinal microsomes from monkeys and humans. In hepatic microsomes, levels of oxidation activities were similar between the two monkey species, and substrate enantioselectivity (R-PL<S-PL) was observed in the formation of 5-OH-PL and/or NDP. Kinetic experiments revealed that the formation of all metabolites was biphasic in cynomolgus monkeys, whereas only the formation of NDP was biphasic in marmosets. Inhibition experiments employing human CYP antibodies and chemical inhibitors suggested that mainly CYP2D enzymes and partially CYP1A and 2C enzymes are involved in the oxidation of PL in both monkey liver microsomes. In small intestinal microsomes, activity levels were much higher in cynomolgus monkeys than in marmosets and humans and reversed substrate enantioselectivity (R-PL>S-PL) was seen in the formation of NDP in cynomolgus monkeys and humans and in the formation of 5-OH-PL in marmosets. The formation of the three metabolites in cynomolgus monkeys and the formation of NDP in marmosets were biphasic, while the formation of 4-OH-PL in humans was monophasic. From the inhibition experiments using CYP antibodies, CYP2C9 and 2C19 were thought to be involved as N-deisopropylases and CYP2D6 and 3A4 as 4-hydroxylases in human small intestine. Furthermore, CYP1A, 2C and 3A enzymes could be involved in cynomolgus monkeys and CYP2C and 3A enzymes in marmosets. These results indicate that the oxidative profile of PL in hepatic and small intestinal microsomes differ considerably among cynomolgus monkeys, marmosets and humans.
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
Takeshi
T
Shimizudani
Kenjiro
K
Nagaoka
Nobumitsu
N
Hanioka
Shigeru
S
Yamano
Shizuo
S
Narimatsu
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D002144:Callithrix; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008252:Macaca fascicularis; D008861:Microsomes / Q000201:enzymology*; D010084:Oxidation-Reduction; D011433:Propranolol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013237:Stereoisomerism
D000906:Antibodies; C400322:cytochrome P-450 CYP2C subfamily; C012878:N-desisopropylpropranolol; C001422:4-hydroxypropranolol; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol