Enantioselective metabolism of propanolol in isolated hepatocytes prepared from untreated, PB- or 3-MC-pretreated rats.
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 microM PL (RS-PL, R(+)-PL or S(-)-PL) was incubated at 37 degrees C using 8 x 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 degrees 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 (microliter/min.8 x 10(6) cells), the easiest formation of NDP from R(+)-PL was observed in the rat hepatocyte system pretreated with 3-MC.
Department of Biopharmaceutics, Kyushu University Graduate School of Pharmaceutical Sciences, Higashi-ku, Fukuoka 812-8582, Japan.
X
X
Wu
A
A
Noda
H
H
Noda
S
S
Eto
H
H
Muro
Y
Y
Ono
K
K
Inokuchi
D000818:Animals; D002478:Cells, Cultured; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D011433:Propranolol / Q000378:metabolism*; D051381:Rats
D011433:Propranolol