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Acanthopanax senticosus HARMS (AS) is used as a Chinese herbal medicine and as a health supplement in Japan. However, little is known about the interaction between AS and other drugs. In this study, we investigated the effect of AS extract on intestinal drug transporter (P-glycoprotein, or P-gp) and peptide transporter activities in Caco-2 cells. Caco-2 cells were cultured on a culture dish and a permeable membrane for 1-3 weeks. The apical-to-basolateral (A-to-B) transport of digoxin, a P-gp substrate, was significantly increased by the addition of AS extract in a concentration-dependent manner. In contrast, the A-to-B transport of cephalexin, a peptide transporter substrate, was significantly decreased by the addition of AS extract in the same manner. The effects of AS extract addition on the kinetics of the uptake of rhodamine 123, a P-gp substrate, and Gly-Sar, a peptide transporter substrate, were investigated. V (max) for rhodamine 123 uptake was significantly increased by AS extract addition compared with the control, whereas that for Gly-Sar uptake was significantly decreased. On the other hand, K (m) and K (d) for rhodamine 123 and Gly-Sar uptake were not affected. We conducted further investigations to clarify the effect of AS extract addition on P-gp activity. When AS extract was added to the apical side, B-to-A transport of rhodamine 123 was significantly decreased compared with the control. Furthermore, the amount of intracellular rhodamine 123 was increased by AS extract addition compared with the control. These results suggest that P-gp and peptide transporter activities are suppressed by AS extract addition in a non-competitive manner.

2004-01-01·Biological and Pharmaceutical Bulletin4区 · 医学

Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

4区 · 医学

Article

作者: Satoh, Takashi ; Itoh, Shungo ; Yoshizawa, Itsuo ; Tomikawa, Yuki ; Takanashi, Kaori ; Itoh, Shinji

To determine the inhibition effects of drugs on the glucuronidation of estradiol (E2), 29 drugs that have been reported to induce gynecomastia were examined in the presence of UDP-glucuronic acid using human hepatic microsomes (pooled) as the enzyme source. The percentage inhibition of the E2 glucuronidation was determined at drug concentrations of 1 microM (approximate therapeutic concentration) and 100 microM (non-clinical overdose concentration) based on the rate constants for the 3- and 17-glucuronidation of E2 (11.2 and 2.52 pmol/min/mg protein, respectively). The only drug that exhibited 50% or higher inhibition of the 3-glucuronidation at a concentration of 1 microM was manidipine (54.4%). When the concentration was 100 microM, manidipine exhibited 100% inhibition of the 3-glucuronidation, and other drugs that exhibited 50% or higher inhibition of the 3-glucuronidation were nicardipine (92%), nisoldipine (90%), nifedipine (84%), domperidone (81%), tacrolimus (80%), nitrendipine (77%) and ketoconazole (69%). Conversely, ipriflavone accelerated the formation of estradiol 3-glucuronide in the activity of 165% at the concentration of 100 microM. On the 17-glucuronidation, all of the drugs showed less than 50% inhibition at the concentration of 1 microM, but at the concentration of 100 microM, drugs that exhibited 50% or higher inhibition consisted of manidipine (79%), chlormadinone acetate (74%), nisoldipine (66%), nitrendipine (60%) and ketoconazole (55%). Although IC(50) values of these drugs were all lower than the K(m) value (285 microM) for the 3-glucuronidation of E2, they were higher than the K(m) value for the 17-glucuronidation (18.8 microM). Thus, the effect of the drugs on the E2 glucuronidation should be greater for hydroxy group at the C-3 than that at the C-17 of E2 molecule. On the other hand, metabolic clearances (V(max)/K(m)) of the 3- and 17-glucuronidation were about 1/14th and 1/18th of that of the 2-hydroxylation of E2, respectively. The result implies that, when the contribution of the glucuronidation to enterohepatic circulation is taken into consideration, the effect of this metabolic inhibition in the estrogen pool cannot be ignored.

Horumon to Rinsho

Drug-induced gynecomastia and its mechanism

作者: Satoh, Takashi ; Yoshizawa, Itsuo

A review on drugs inducing gynecomastia, formation and metabolism of estradiol, and drugs affecting hydroxylation, glucuronidation, etc., of estradiol.

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