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Stereoselective propranolol metabolism in two drug induced rat hepatic microsomes

Xin Li, Su Zeng

    World Journal of Gastroenterology
    |January 31, 2002
    PubMed

    Insights

    Inducers like benzoflavone (BNF) and phenobarbital (PB) alter rat liver enzyme activity, affecting how propranolol enantiomers are metabolized. BNF enhances R(+)propranolol metabolism, while PB affects S(-)propranolol metabolism, indicating altered stereoselectivity.

    Area of Science:

    • Pharmacology and Toxicology
    • Drug Metabolism and Pharmacokinetics
    • Enzymology

    Background:

    • Propranolol is a beta-blocker with chiral properties, existing as R(+) and S(-) enantiomers.
    • Hepatic microsomal enzymes, particularly cytochrome P450 (CYP) isoforms, are crucial for drug metabolism.
    • Enzyme inducers like 3-methylcholanthrene (BNF) and phenobarbital (PB) can alter CYP expression and activity, potentially influencing stereoselective drug metabolism.

    Purpose of the Study:

    • To investigate the impact of BNF and PB induction on the stereoselective metabolism of propranolol in rat hepatic microsomes.
    • To characterize the kinetic parameters (Km, Vmax, Clint) of propranolol enantiomers in control and induced microsomes.
    • To elucidate the role of specific CYP subfamilies in the stereoselective metabolism of propranolol.

    Main Methods:

    • Rat hepatic microsomes were prepared from control, BNF-induced, and PB-induced rats.
    • Phase I metabolism of R(+) and S(-) propranolol was studied using these microsomes.
    • Enzymatic kinetic parameters were determined via Lineweaver-Burk plot analysis, and propranolol concentrations were quantified using High-Performance Liquid Chromatography (HPLC).

    Main Results:

    • A validated RP-HPLC method was established for accurate propranolol enantiomer quantification.
    • BNF induction significantly enhanced the intrinsic clearance (Clint) of R(+)propranolol, while PB induction primarily affected S(-)propranolol metabolism.
    • Enzyme kinetic analysis revealed altered catalytic abilities (Vmax and Clint) for both enantiomers across different induction states, indicating stereoselective changes in metabolism.

    Conclusions:

    • BNF and PB induction alter the composition and regioselectivity of hepatic microsomal enzyme activity centers.
    • The observed stereoselectivities in propranolol metabolism are attributed to the stereoselective catalytic functions of induced enzymes.
    • CYP1A subfamily (induced by BNF) shows a pronounced stereoselective contribution to R(+)propranolol metabolism, while CYP2B subfamily (induced by PB) contributes moderately to S(-)propranolol metabolism.

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