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可能发生的药代动力学变化，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、各种女性性激素对地高辛吸收的调节作用、p -糖蛋白参与各种新型喹诺酮类药物吸收的情况。女性受试者月经周期0-4天和11-13天口服加替沙星后血浆LH水平与血浆浓度的关系。本研究结果总结如下：1)女性受试者在月经周期的4个不同时期口服地高辛（0.25 mg），其血药浓度-时间分布差异很大，第12、23、27天的C_<max>值明显高于第4天。第12和23天的K_a值分别是第4天的4倍和2.5倍。第12天和第23天的T_<max>值比第4天短。这些结果表明地高辛的吸收或分布可能在月经周期中发生显著变化。2)黄体生成素（LH）与地高辛共给药及静脉给药均显著增加地高辛对大鼠肠袢的吸收。然而，卵泡刺激素、雌二醇和黄体酮在调节地高辛吸收方面远不如LH有效。众所周知，血浆LH浓度在月经周期的第12天左右显著增加，这些结果很好地支持地高辛吸收在月经周期的第12天显着调节的发现。3)采用原位环法和扩散室法评价p -糖蛋白在大鼠体内对各种新型喹诺酮类药物吸收中的作用。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。因此，与地高辛相比，加替沙星或洛美沙星是评价p -糖蛋白底物在月经周期药代动力学变化的良好模型。4)女性受试者在月经周期第0-4天（M_<0-4>）和第11-13天（M_<11-13>）口服加替沙星（200 mg），与M_<0-4>相比，M_<11-13>时Cmax升高，AUC0-8升高。血浆LH浓度之比（LH_<11-13>/LH_<0-4>）与AUC之比（AUC_<11-13>/AUC_<0-4>）之间存在相关性。我们目前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波动，特别是由于血浆LH浓度的显著升高。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