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The popularity of traditional herbal medicine (THM) being used as complementary medicines or alternative medicines is increasing. On the other hand, the development of multidrug resistance (MDR) remains a major hurdle to successful cancer chemotherapy. Some THMs capable of reversing MDR may contribute to the improvement of clinical outcomes in cancer chemotherapy. Herein, 19 kinds of herb were chosen from the ingredients of major THMs, and their effects on the sensitivity to anticancer drugs of tumor cells were investigated using the human cervical carcinoma HeLa cells. Focusing on the major mechanism for MDR, i.e., MDR1/P-glycoprotein, the effects of herbal extracts on its transport function were also examined using a MDR1 substrate Rhodamine123. Glycyrrhizae Radix, Rhei Rhizoma, Scutellariae Radix, Poria, Zizyphi Fructus, Zingiberis Rhizoma (dry), Coptidis Rhizoma, Ephedrae Herba and Asiasari Radix significantly enhanced the sensitivity to a MDR1 substrate paclitaxel, whereas none of the herbal extracts used had any effect on the sensitivity to 5-fluorouracil, which is not a substrate for MDR1. Rhodamine123 uptake was significantly increased by Rhei Rhizoma, Poria or Ephedrae Herba among nine herbal extracts sensitized to paclitaxel. This suggests that the increase in paclitaxel sensitivity by Glycyrrhizae Radix, Rhei Rhizoma, Poria or Ephedrae Herba was caused, in part, by the inhibition of MDR1 function, and the change in paclitaxel sensitivity by the other herbal extracts was not always dependent on this. Collectively, these findings indicate that the combination of anticancer drugs with some herbal extracts contributes to the enhancement of clinical outcomes in cancer chemotherapy.

The effects of Ginkgo biloba leaf extract (GBE), a widely used herbal dietary supplement in Japan, on the pharmacokinetics and pharmacodynamics of nifedipine (NFP), a calcium-channel blocker, were studied using 8 healthy volunteers. Simultaneous oral ingestion of GBE (240 mg) did not significantly affect any of the mean pharmacokinetic parameters of either NFP or dehydronifedipine, a major metabolite of NFP, after oral administration of NFP (10 mg). However, the maximal plasma NFP concentrations in 2 subjects were approximately doubled by GBE, and they had severer and longer-lasting headaches with GBE than without GBE, with dizziness or hot flushes in combination with GBE. The mean heart rate after oral administration of NFP with GBE tended to be faster than that without GBE at every time point. Accordingly, it was concluded that GBE and NFP should not be simultaneously ingested as much as possible, and careful monitoring is needed when administering NFP concomitantly with GBE to humans.

The aim of our study was to investigate the effects of rabeprazole, a proton pump inhibitor, on MDR1 expressed on human colon carcinoma cell line, Caco-2, and MDR1-overexpressing human cervical carcinoma cell line, HeLa cells selected by exposure to 100 nM vinblastine (Hvr100-6 cells). Inhibitory effects of rabeprazole on MDR1-mediated transport of Rhodamine123 were examined in these cells. A thousand micro molar rabeprazole increased Rhodamine 123 uptakes in Caco-2 and Hvr100-6 cells by 68% and 185%, respectively. No significant effects of rabeprazole were observed at the concentration of 1-100 microM. Since rabeprazole did not show any effects on Rhodamine 123 transport via MDR1 at the plasma levels (approximately 1 microM), it was considered that the drug interaction with MDR1 substrates would be minimal even though the interaction occurred in the patients with rabeprazole treatment.

The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan, on the pharmacokinetics of diltiazem (DTZ), a typical probe of cytochrome P450 (CYP) 3A, were examined in rats. The simultaneous addition of GBE to small intestine and liver microsomes inhibited the formation of N-demethyl DTZ (MA), an active metabolite of DTZ produced by CYP3A, in a concentration-dependent manner, with an IC(50) of about 50 and 182 microg/ml, respectively. This inhibition appeared to be caused, at least in part, by a mechanism-based inhibition. Both the rate of formation of MA and total amount of CYP in intestinal or hepatic microsomes after a single oral pretreatment with GBE (20 mg/kg) decreased transiently. The pretreatment significantly decreased the terminal elimination rate constant and increased the mean residence time, after intravenous administration of DTZ (3 mg/kg). Furthermore, it significantly increased the area under the concentration-time curve and absolute bioavailability after oral administration of DTZ (30 mg/kg). These results indicated that the concomitant use of GBE in rats increased the bioavailability of DTZ by inhibiting both intestinal and hepatic metabolism, at least in part, via a mechanism-based inhibition for CYP3A.

The possibility of pharmacokinetic interactions between Sho-saiko-to extract powder (TJ-9), the most widely used traditional Chinese herbal (Kampo) medicine in Japan, and carbamazepine (CBZ), an important anti-epileptic drug, was examined in rats. There was no significant difference in the protein binding of CBZ in serum obtained before and after the single oral administration of TJ-9. The addition of TJ-9 to normal hepatic microsomes inhibited CBZ-10,11-epoxylase activity in a concentration-dependent manner. Liver weight, amounts of P450 and cytochrome b(5) in hepatic microsomes and the formation of carbamazepine-10,11-epoxide (CBZ-E), an active metabolite of CBZ, by microsomes were not influenced by 2-week repeated oral pretreatment with TJ-9 (1 g/kg/d), although pretreatments with phenobarbital (80 mg/kg/d, i.p.) significantly increased these parameters. The simultaneous oral administration of TJ-9 (1 g/kg) significantly decreased the peak plasma concentration of CBZ and the area under the concentration-time curve of CBZ-E, and lengthened the time to reach the peak concentration of CBZ after oral administration of CBZ. Two-week repeated oral pretreatment with TJ-9, however, did not affect the plasma concentration-time profile or any pharmacokinetic parameter of CBZ or CBZ-E. Also, a single oral administration of TJ-9 (1 g/kg) significantly delayed gastric emptying. These results indicated that the simultaneous oral administration of TJ-9 with CBZ to rats decreased the gastrointestinal absorption of CBZ, at least in part, by delaying gastric emptying, without affecting the metabolism of CBZ.

The effects of oral co- and pre-administration of Sho-seiryu-to extract powder (TJ-19, 1 g/kg), a widely used Kampo (traditional Chinese herbal) medicine, on the pharmacokinetics of an anti-epileptic drug, carbamazepine (CBZ), and its active metabolite (carbamazepine-10,11-epoxide, CBZ-E) after oral administration of CBZ (50 mg/kg) were examined in male rats. The simultaneous administration of TJ-19 significantly lengthened the time to reach the peak plasma concentration (Tmax), but did not influence the peak plasma concentration, area under the plasma concentration-time curve or terminal elimination half-life (t1/2). Each parameter for CBZ or CBZ-E with a single pretreatment with TJ-19 was not significantly different from that with the vehicle. Tmax and the elimination rate constant for CBZ were significantly increased by 1-week repeated pretreatment with TJ-19, by 83% (p

The characteristics of pirarubicin transport have been investigated in polymorphonuclear leukocytes isolated from rats. The uptake of pirarubicin by leukocytes was time-, temperature- and concentration-dependent with the maximum velocity (Vmax) of 4.84 nmol/5 x 10(6) cells/min and the Michaelis constant (Km) of 13.4 microM. The uptake depended on the extracellular pH, indicating that the molecular form of pirarubicin is more permeable than its ionic form and/or that the transporter of pirarubicin has optimal pH range. When the intracellular space was changed by increasing the medium osmolarity with sucrose, the uptake was altered by osmolarity changes and it appeared that about 27% of the drug was bound to the membrane surface. The initial uptake was inhibited by the metabolic inhibitors rotenone, 2,4-dinitrophenol and sodium cyanide. Pirarubicin accumulation in the intracellular glucose-depleted cells diminished significantly compared with that in normal cells. The efflux of pirarubicin from leukocytes was also temperature-dependent and inhibited by a metabolic inhibitor. These results indicate that a specific mechanism is concerned in the transport of pirarubicin in polymorphonuclear leukocytes.