怀孕会影响西地那非及其代谢物在兔子体内的药代动力学。

Pregnancy affects the pharmacokinetics of sildenafil and its metabolite in the rabbit.

Russo Francesca M, Mian Paola, Krekels Elke H, Van Calsteren Kristel, Tibboel Dick, Deprest Jan, Allegaert Karel

a Cluster Woman and Child, Department of Development and Regeneration, Biomedical Sciences, KU Leuven , Leuven , Belgium.

b Department of Obstetrics and Gynecology , University Hospitals Leuven , Leuven , Belgium.

Xenobiotica. 2019 Jan;49(1):98-105. doi: 10.1080/00498254.2017.1422217. Epub 2018 Jan 10.

Abstract

There is growing interest in the use of sildenafil during pregnancy for various maternal and fetal conditions. This study aims to investigate the effect of pregnancy on the maternal pharmacokinetics (PK) of sildenafil and its main metabolite desmethylsildenafil in rabbits. Using NONMEM, population PK modeling was performed based on plasma samples from 31 rabbits of whom 15 were pregnant and 16 were not. All received a single subcutaneous sildenafil dose of 10 mg/kg. One sample was obtained per rabbit at either 30, 60, 120, 360, 720 or 1320 min after sildenafil administration. 2. A two- and one-compartment PK-model best described the data for sildenafil and desmethylsildenafil, respectively. Compared to non-pregnant rabbits, the central and peripheral volume of distribution and inter-compartmental clearance of sildenafil were lower in pregnant rabbits [32.1 versus 12.2 L, 110 versus 44.4 L and 25.5 versus 12.1 L/h; all p < 0.05]. The formation clearance from sildenafil to desmethylsildenafil was also reduced during pregnancy [13.3 versus 7.8 L/h; p < 0.05]. 3. In contrast, the elimination clearance of desmethylsildenafil, was higher in pregnancy [73.5 versus 116. 9; p < 0.05]. In rabbits, pregnancy impacts PK parameters of sildenafil and its metabolite, leading to an increased peak concentration and 24 h exposure for sildenafil and a decreased 24 h exposure for desmethylsildenafil.

摘要

孕期使用西地那非治疗各种母体和胎儿疾病的关注度日益增加。本研究旨在探讨妊娠对家兔体内西地那非及其主要代谢产物去甲基西地那非母体药代动力学（PK）的影响。使用NONMEM软件，基于31只家兔的血浆样本进行群体PK建模，其中15只为妊娠家兔，16只为非妊娠家兔。所有家兔均接受10mg/kg的单次皮下西地那非给药。在西地那非给药后30、60、120、360、720或1320分钟，从每只家兔采集一份样本。2. 二室和一室PK模型分别最能描述西地那非和去甲基西地那非的数据。与非妊娠家兔相比，妊娠家兔中西地那非的中央室和外周室分布容积以及室间清除率较低[分别为32.1对12.2L、110对44.4L和25.5对12.1L/h；均p<0.05]。妊娠期间从西地那非到去甲基西地那非的生成清除率也降低了[13.3对7.8L/h；p<0.05]。3. 相比之下，妊娠时去甲基西地那非的消除清除率较高[73.5对116.9；p<0.05]。在家兔中，妊娠会影响西地那非及其代谢产物的PK参数，导致西地那非的峰浓度和24小时暴露量增加，而去甲基西地那非的24小时暴露量减少。