| Project/Area Number |
15590136
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido |
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Principal Investigator |
SAITOH Hiroshi Health Sciences University of Hokkaido, Professor, 薬学部, 教授 (30285522)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Michiya Health Sciences University of Hokkaido, Associate Professor, 薬学部, 助教授 (60337029)
ODA Masako Health Sciences University of Hokkaido, Research Associate, 薬学部, 助手 (60204210)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Menstrual cycle / P-glycoprotein / Digoxin / Pharmacokinetics / Luteinizing hormone / Gatifloxacin / Intestinal secretion / New quinolones / 性周期関連ホルモン / 卵胞刺激ホルモン / 薬物体内動態 / ジゴキシン吸収 / 体内動態変化 |
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| Research Abstract |
In order to know the possible changes in pharmacokinetics of P-glycoprotein substrates dining the menstrual cycle, we investigated the plasma concentrations of digoxin after oral administration to female subject during different stages of menstrual cycle, the modulating effect of various female sex hormones on the absorption of digoxin, the involvement of P-glycoprotein in the absorption of various new quinolones, and the relationship between plasma LH levels and plasma gatifloxacin concentrations after its oral administration to female subjects on 0-4 day and 11-13 day of their menstrual cycles. The results obtained in this study are summarized as follows:
1) When a female subject orally received digoxin (0.25 mg) during the four different phases of her menstrual cycle, the plasma concentration-time profiles were widely different The C_<max> values on day 12,23, and 27 were markedly higher than that on day 4. The K_a values on day 12 and 23 were approximately 4-and 2.5-fold greater tha
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n that on day 4. The T_<max> values on day 12 and 23 were shorter than those on day 4. These results suggested a possibility that digoxin absorption or distribution remarkably varies during menstrual cycle.
2) Luteinizing hormone (LH) significantly increased the absorption of digoxin from rat intestinal loops when it was coadministered with digoxin into the loops and when it was administered intravenously to rats. However, follicle-stimulating hormone, estradiol, and progesterone were much less potent than LH in modulating the absorption of digoxin. As it is known that plasma LH concentrations increased markedly on around 12 day of a menstrual cycle, these results well supported the findings that digoxin absorption is significantly modulated on day 12 of the menstrual cycle.
3) The involvement of P-glycoprotein in the absorption of various new quinolones was evaluated in rats using in situ loop technique and diffusion chambers. It was shown that the absorption of gatifloxacin and lomefloxacin was significantly interfered with P-glycoprotein. Thus, gatifloxacin or lomefloxacin is a good model to evaluate the changes in pharmacokinetics of P-glycoprotein substrate during the menstrual cycle alternative to digoxin.
4) When gatifloxacin (200 mg) was orally administered to female subjects on day 0-4 (M_<0-4>) and day 11-13 (M_<11-13>) during their menstrual cycles, the Cmax elevated and AUC0-8 increased on M_<11-13> compared with M_<0-4>. On the other hand, Tmax was shorted on M_<11-13> compared with M_<0-4> There was a correlation between the ratio of plasma LH concentration (LH_<11-13>/LH_<0-4>) and the ratio of AUC (AUC_<11-13>/AUC_<0-4>).
The findings obtained from our present study strongly suggest that the pharmacokinetics of P-glycoprotein substrates would fluctuate during the menstrual cycle, especially due to the striking elevation of plasma LH concentrations. Less
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