Effect of menstrual cycle on the pharmacokinetics of P-glycoprotein substrates

为了了解P-糖蛋白底物在月经周期中的药代动力学变化，我们研究了女性受试者在月经周期不同阶段口服地高辛后的血药浓度，不同女性性激素对地高辛吸收的调节作用，P-糖蛋白在各种新喹诺酮类药物吸收中的作用，以及女性受试者在月经周期0-4天和11-13天口服地高辛后血浆黄体生成素水平与血浆加替沙星浓度的关系。研究结果如下：1)女性受试者在月经周期的四个不同阶段口服地高辛0.25mg时，血药浓度-时间曲线差异很大，第12、23、27天的血药浓度-时间曲线Cmax和Gt；显著高于第4天。第12天和第23天的K_a值约为…的4倍和2.5倍12天和23天的T_&lt；max和Gt；值均小于第4天。这些结果表明，地高辛在月经周期中的吸收或分布可能有显著的变化。2)黄体生成素与地高辛合用时和静脉给药时，可显著增加地高辛在大鼠肠道的吸收。然而，促卵泡激素、雌二醇和黄体酮在调节地高辛的吸收方面远不如黄体生成素有效。已知血浆黄体生成素浓度在月经周期的第12天左右显著升高，这些结果很好地支持了这一发现，即地高辛的吸收在月经周期的第12天受到显著调节。3)利用原位环技术和扩散箱评估P-糖蛋白在大鼠体内对各种新的喹诺酮类药物的吸收。结果表明，P-糖蛋白对加替沙星和洛美沙星的吸收有明显的干扰作用。因此，加替沙星或洛美沙星是评价P-糖蛋白底物在月经周期替代地高辛的药代动力学变化的良好模型。4)女性受试者在月经周期的第0-4天(M_&lt；0-4&gt；)和第11-13天(M_&lt；11-13&gt；)口服加替沙星(200 Mg)，其Cmax和AUC0-8较M_&lt；0-4&Gt；血浆黄体生成素浓度比值与AUC比值(AUC_&lt；11-13&gt；/AUC_&lt；0-4&gt；)呈正相关。我们的研究结果强烈表明，P-糖蛋白底物的药代动力学在月经周期中会发生波动，特别是由于血浆促黄体生成素浓度的显著升高。较少

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 … More 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