Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
J Clin Pharmacol. 2021 Apr;61(4):472-479. doi: 10.1002/jcph.1751. Epub 2020 Sep 25.
Midazolam is an established probe drug to assess cytochrome P450 3A activity (phenotyping). Microdosed midazolam is increasingly used for this purpose; a buccal formulation might be of advantage, but buccal absorption might occur. We therefore tested in a single-center, open-label clinical trial with 12 healthy volunteers the absolute bioavailability of 10 μg of midazolam after buccal administration in relation to buccal exposure time. In relation to a drinking solution, there was an increase of midazolam exposure (area under the plasma concentration-time curve from time 0 to infinity) with increasing buccal exposure time with an apparent saturation at 100-second buccal exposure. Absolute bioavailability increased from 27.8% (95% confidence interval, 23.5-32.9) for the drinking solution (0 seconds) to 66.1% (95% confidence interval, 60.0-72.8) after 100-second buccal exposure with no further increase after 150 seconds. A Hill equation described the time dependency of midazolam bioavailability with maximal bioavailability as 64.5% and buccal exposure time resulting in half maximal bioavailability increase as 16 seconds. In conclusion, midazolam bioavailability is highly dependent on buccal exposure time, and even a few seconds of buccal exposure will increase bioavailability due to buccal absorption. This needs to be taken into account for any buccal administration of midazolam.
咪达唑仑是评估细胞色素 P4503A 活性（表型）的既定探针药物。微剂量咪达唑仑越来越多地用于此目的；颊部制剂可能具有优势，但可能会发生颊部吸收。因此，我们在一项单中心、开放标签的临床试验中，在 12 名健康志愿者中测试了 10μg 咪达唑仑颊部给药后与颊部暴露时间相关的绝对生物利用度。与饮用溶液相比，随着颊部暴露时间的增加，咪达唑仑暴露量（从 0 到无穷大的血浆浓度-时间曲线下面积）增加，在 100 秒颊部暴露时出现明显饱和。绝对生物利用度从饮用溶液（0 秒）的 27.8%（95%置信区间，23.5-32.9）增加到 100 秒颊部暴露后的 66.1%（95%置信区间，60.0-72.8），150 秒后无进一步增加。Hill 方程描述了咪达唑仑生物利用度随时间的依赖性，最大生物利用度为 64.5%，导致生物利用度增加一半的颊部暴露时间为 16 秒。总之，咪达唑仑的生物利用度高度依赖于颊部暴露时间，即使是几秒钟的颊部暴露也会由于颊部吸收而增加生物利用度。这需要考虑到任何咪达唑仑的颊部给药。
