In-vitro Metabolic Interaction of Bunitrolol Enantiomers in Rabbit Liver Microsomes

Shizuo Narimatsu, Takao Mizukami, Yong Huang, Yasuhiro Masubuchi, Tokuji Suzuki

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8 Citations (Scopus)


We have examined the 4-hydroxylation of bunitrolol in rabbit and rat liver microsomes. Significant species differences (rabbit rat of both sexes) and sex (male > female of both species) were observed in the formation of 4-hydroxybunitrolol from racemic bunitrolol (10 μM). The 4-hydroxylation of bunitrolol racemate and enantiomers showed biphasic kinetics, a low-Km system and a high-Kmax system, in liver microsomes from rabbits of both sexes. There were significant differences in Km and Vmax values [(+) > (-)] for 4-hydroxylations of (+)-bunitrolol and (-)-bunitrolol in the low-Km system. Furthermore, the rate of clearance (Vmax/Km) was 20- to 200-fold for the low-Km system compared with the high-Km system, indicating that enzymes in the low-Km system play a major part in the rabbit liver microsomal bunitrolol metabolism. Inhibition studies using cytochrome P450 inhibitors such as quinidine, quinine, and α-naphthoflavone or polyclonal antibodies raised against rat P450-2D and -1A enzymes did not make clear which P450 enzymes are involved in bunitrolol 4-hydroxylation in rabbit liver microsomes. The 4-hydroxylase activity of (+)-bunitrolol was slightly higher than that of (-)-bunitrolol in separated incubations containing male rabbit liver microsomes and an enantiomer concentration of 10 μM. However, the 4-hydroxylation of (+)-bunitrolol (10μM) was markedly suppressed in the presence of its antipode (10 μM), whereas (-)-bunitrolol 4-hydroxylation was not affected by the presence of its antipode, resulting in a change of the stereoselectivity from (+) > (-) for enantiomer to (+) < (-) for racemate. The difference in the Michaelis constants in the low-Km system, where the Km value of (-)-bunitrolol is one-eighth that of (+)-bunitrolol, is thought to cause the change in the stereoselectivity in rabbit liver microsome-mediated bunitrolol 4-hydroxylation.

Original languageEnglish
Pages (from-to)1185-1189
Number of pages5
JournalJournal of Pharmacy and Pharmacology
Issue number11
Publication statusPublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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