The present paper describes the metabolism of a chiral drug propranolol (PL) using isolated hepatocytes freshly prepared from untreated, PB- or 3-MC-pretreated rats. In order to examine not only the existence of enantioselectivity but also the effect of enzyme inducer (PB or 3-MC) on PL metabolism, 500 μM PL (
RS-PL,
R(+)-PL or
S(–)-PL) was incubated at 37°C using 8×10
6 cells/ml isolated rat hepatocytes. Then, the elimination amount of PL and the formation amounts of eight kinds of the metabolites including ring hydroxylated metabolites (4-OH-, 5-OH- and 7-OH-PL) and side chain metabolites (NDP, AcNDP, PGL, NLA and NAA) were simultaneously determined by HPLC. By 3-MC- and PB-pretreatment, a significant increase was noticed in PL elimination and also in the formation of PL metabolites, NDP, NLA and NAA. Furthermore, the presence of enantioselectivity was observed,
i.e. the substrate
R(+)-PL was always eliminated faster than the substrate
S(–)-PL. Regarding the metabolite formation, NDP, AcNDP and NAA were dominantly produced from
R(+)-PL, and NLA, PGL and the ring hydroxylated metabolites from
S(–)-PL. In all cases of PL elimination and the metabolite formation, the amounts of the metabolites derived from
RS-PL indicated the mean values of the respective amounts derived from
R(+)-PL and
S(–)-PL. Using the three kinds of isolated rat hepatocytes mentioned above, the kinetic parameters of NDP-formation at 37°C for 10 min were calculated using
RS-PL,
R(+)-PL or
S(–)-PL as a substrate. From the pseudo values of
V′max/
K′m (μl/min・8×10
6 cells), the easiest formation of NDP from
R(+)-PL was observed in the rat hepatocyte system pretreated with 3-MC.
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