Studies on interactions between traditional herbal and western medicines. IV: Lack of pharmacokinetic interactions between Saiko-ka-ryukotsu-borei-to and carbamazepine in rats

Abstract

The possibility of pharmacokinetic interactions between Saiko-ka-ryukotsu-borei-to extract powder (TJ-12), a widely used traditional Chinese herbal (Kampo) medicine, and carbamazepine (CBZ), an important anti-epileptic drug, was examined in rats. There were no significant differences in the serum protein binding of CBZ and carbamazepine- 10,11-epoxide (CBZ-E), its active metabolite, at two concentrations (1 and 10 Bg/ml) between twogroups pretreated orally with the vehicle andTJ-12 suspension (1 g/kg/d, p.o.) for 1 week. One-week repeated pretreatment with TJ- 12 (1 g/kg/d) did not influence liver weight, contents of cytochromes P450 and b5 in hepatic microsomes or the formation rate of CBZ-E from CBZ by its microsomes, while pretreatment with phenobarbital (80 mg/kg/d, i.p.) significantly increased these parameters. Neither a single nor 1-week repeated oral pretreatment with TJ-12 (1 g/kg/d) affected the plasma concentration-time profile and any pharmacokinetic parameter of CBZ or CBZ-E after oral administration of CBZ (50 mg/kg). These results indicated that oral co-administration of TJ-12 with CBZ has no effect ofthe pharmacokinetics of CBZ or CBZ-E in rats. Concomitant treatment with TJ- 12 and CBZ appears to be pharmacokinetically safe in humans.

Studies on Interactions between Traditional Herbal and Western Medicines. V. Effects of Sho-saiko-to (Xiao-Cai-hu-Tang) on the Pharmacokinetics of Carbamazepine in Rats.

“…The protein binding rates of CBZ (about 82%) were similar to those reported previously by us. 4,6) Effects of TJ-9 on Hepatic Drug-Metabolizing Enzymes The activity of CBZ-10,11-epoxylase against hepatic microsomes obtained from normal rats was significantly reduced by the addition of TJ-9, the inhibitory action being concentration-dependent (Fig. 1).…”

“…4,6) Preparation of Liver Microsomes Hepatic microsomes were prepared using normal rats or rats pretreated separately with a 2% (w/v) arabic gum solution (vehicle), TJ-9 suspension and PB-saline solution. Briefly, the vehicle (p.o.…”

“…8) The rate of formation of CBZ-E from CBZ by microsomes was determined with or without various concentrations of TJ-9 (100, 500 or 1000 mg/ml) or erythromycin (2 mM) in the same manner, which we reported previously. 6) Final concentrations of microsomal protein and CBZ were 0.5 mg/ml (final volume of incubation medium: 0.3 ml) and 0.1 mM, respectively, and the incubation time and temperature were 5 min and 37°C, respectively.…”

“…6) Pharmacokinetic Analysis The peak plasma concentration (C max ) and the time to reach C max (T max ) of CBZ and CBZ-E were obtained from the actual data observed after oral administration. The terminal elimination rate constant (l) was calculated by fitting individual data for three terminal points of the plasma concentration profile with a log-linear regression equation using the least-squares method.…”

“…TJ-9 (0.125-0.5 g/kg) has been reported to have no inhibitory effects on the gastric emptying rate (GER). 19) Nishimura et al 20) however, reported that TJ-9 (0.25-0.75 g/kg) delayed gastric emptying without regard to the increase of intragastric pH and consequently could decrease gastrointestinal absorption of tolbutamide, speculating that it may be caused by [6]-gingerol, a component of Zingiberis Rhizome which is one of 7 kinds of constituents in TJ-9.…”