No abstract

The Kampo medicines are more and more often used in recent years, usually together with the Western drugs. The need for the investigation of drug interactions between Kampo medicines and Western drugs are, therefore, widely recognized. In the present study, the effects of 3 Kampo medicines (Rikkunshito, Yokukansan and Boiogito) on the activity of cytochrome P450 (CYP), a superfamily of drug-metabolizing enzymes, were investigated in an in vitro study using human CYP recombinants. Their effects on the P-glycoprotein (P-gp), one of the major drug transporters, were also evaluated by the ATPase assay using human P-gp membranes and verapamil as a substrate. The inhibition rate of Rikkunshito, Yokukansan and Boiogito on human CYP3A4, 2C9, 2C19, 2D6 and 2E1 was less than 50% at the concentrations below 0.1 mg/ml except for the inhibition of CYP2D6 by Boiogito. Furthermore, none of the Kampo medicines affected the ATPase activity at the concentrations lower than 0.1 mg/ml, either in the absence or presence of verapamil, indicating their low inhibitory potency against P-gp. These findings indicate that Rikkunshito, Yokukansan and Boiogito are unlikely to cause clinically relevant drug interactions involving the inhibition of major CYP isozymes and P-gp.

A serious drawback of tumor necrosis factor ␣ (TNF) as a clinical antitumor agent is that it also has hypotensive activity. To overcome this problem, derivatives of its sister cytokine lymphotoxin (TNF-␤ or LT) were prepared. One of them, mutein 2 (Mut2) has a deletion of amino acids 1-7 but contains substituted amino acids, Met-Phe-Pro at positions 8-10 of the mature human LT. This mutein has no hypotensive activity at the maximum dose (10 mg͞kg) tested on rats. In contrast, a much lower dose (1 mg͞kg) of TNF and LT caused a significant blood pressure drop. In vivo studies revealed that Mut2 was more effective than TNF or LT against MethA (a mouse tumor line) as judged by the therapeutic ratio [calculated as LD 50 (dose that kills 50% of the animals)͞ED 50 (dose that reduces the tumor size by 50%)]. With five other different mouse tumors and two different human tumors, Mut2 was also effective and the effectiveness was comparable or superior to that of TNF or LT. These results suggest the possibility that this derivative may be usable as a clinical antitumor agent without the serious side effects associated with TNF.Various attempts have been made to create muteins of tumor necrosis factor (TNF) and lymphotoxin (LT) to improve their therapeutic values (1). Results of these experiments suggest that up to nine NH 2 -terminal amino acids of TNF can be removed without losing cytotoxic activity in vitro (2). The replacement of acidic amino acids at the NH 2 -terminal region with basic amino acids resulted in a better (less toxic with high antitumor activity) TNF (3, 4). Replacement of the COOHterminal region amino acids (amino acids 141-146) with other amino acids often modified the in vitro cytotoxic activity of TNF. The addition of amino acids to TNF at the NH 2 -terminal position decreased a side effect of TNF (enhancement of metastasis) without diminishing its anticancer activity (5).On the other hand, relatively limited information is available for LT because efficient expression in Escherichia coli has become possible only recently (6). In vitro cytotoxic activity was maintained even after removal of the NH 2 -terminal amino acids residues from LT (7). In contrast, the removal of the COOH-terminal region of LT generally resulted in loss of the cytotoxic activity (8). To the best of our knowledge, LT muteins have never been tested in vivo for their antitumor or hypotensive activities.TNF is relatively ineffective against human cancers because its hypotensive activity prevents administration of doses that are high enough to cause tumor regression (9, 10). Systemic use of TNF causes hypotension in the experimental animals (11)(12)(13)(14). In this paper, we describe an LT mutein (mutein 2, Mut2) that lacks hypotensive effects but has high antitumor activity. The ratio hypotensive dose͞therapeutic dose for Mut2 was at least 9-fold higher than that of TNF suggesting the possible future clinical applicability of Mut2. MATERIALS AND METHODSExpression of TNF, LT, and Mut2 in E. coli. TNF and LT genes were clone...

TJ-8117 (Onpi-to) is a herbal medicine extracted from mixture of five crude drugs (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), which has been developed as a drug for chronic renal failure. (-)Epicatechin 3-O-gallate (ECG), one of the active compounds of TJ-8117, was labeled with tritium and spiked to TJ-8117. Effects of food, renal failure and repeated administration to pharmacokinetics of ECG-related radioactivity in the plasma were investigated after oral administration of TJ-8117 containing [3H]ECG ([3H]TJ-8117) in male rats. After oral administration of [3H]TJ-8117, the radioactivity in the plasma in non-fasted rats was higher than that in fasted rats. AUC(0-72 h) and Cmax in the non-fasted was 123% and 248% of those in the fasted. After oral administration of [3H]TJ-8117, the radioactivity in the plasma in 5/6 nephrectomized rats was higher than that in sham-operated rats. AUC(0-72 h) and Cmax in 5/6 nephrectomized was 332% and 236% of those in sham-operated. After repeated administration of TJ-8117 for 6 days, [3H]TJ-8117 was administered on 7th day. Radioactivity in plasma in first day was similar to that in 7th day. The pharmacokinetic parameters were not significantly different between single and repeated administration.