Stereoselectivity in bunitrolol 4-hydroxylation in liver microsomes from marmosets and Japanese monkeys.
The stereoselectivity in 4-hydroxylation of bunitrolol (BTL), a beta-adrenoreceptor blocking agent, was examined in liver microsomes from monkeys (marmosets and Japanese monkeys) and compared with the results of human liver microsomes. The formation of (+)-4-OH-BTL from (+)-BTL from (+)-BTL was significantly higher than that of (-)-4-OH-BTL from (-)-BTL in the liver microsomal fractions from the two kinds of monkeys. The 4-OH-BTL-forming activity from racemic BTL was significantly lower than from enantiomeric BTL, indicating a possible metabolic interaction between BTL enantiomers. The in vitro profiles observed in the monkeys were very similar to those in humans, but the stereoselectivity in BTL metabolism [(+)-BTL > (-)-BTL] in the primates was found to be reverse to that in rats [S. Narimatsu et al., Anal. Biochem., 222, 256-261 (1994)]. The 4-OH-BTL-forming activity from BTL enantiomers was significantly suppressed by quinidine and quinine, while the former was more potent than the latter, and also by alpha-naphthoflavone. Furthermore, the activity was also suppressed by antisera against rat cytochromes P450-2D2 and -1A2 in concentration-dependent manners. However, kinetics showed that enantiomeric BTL 4-hydroxylation was monophasic in liver microsomes from marmosets of both genders and from male Japanese monkeys. These results suggest that cytochrome P450-2D and -1A enzymes with similar Km values are involved in BTL 4-hydroxylation in monkey liver microsomes.
Narimatsu
S
S
Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Gotoh
M
M
Masubuchi
Y
Y
Horie
T
T
Ohmori
S
S
Kitada
M
M
Kageyama
T
T
Asaoka
K
K
Yamamoto
I
I
Suzuki
T
T
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D002144:Callithrix; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000502:physiology; D015786:Cytochromes b5 / Q000032:analysis; D005260:Female; D006801:Humans; D006900:Hydroxylation; D015151:Immunoblotting; D008251:Macaca; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D011412:Propanolamines / Q000378:metabolism*; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; C084811:bunitrolol