Schalkwijk Stein, Greupink Rick, Colbers Angela P, Wouterse Alfons C, Verweij Vivienne G M, van Drongelen Joris, Teulen Marga, van den Oetelaar Daphne, Burger David M, Russel Frans G M
Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
J Antimicrob Chemother. 2016 Feb;71(2):480-3. doi: 10.1093/jac/dkv358. Epub 2015 Nov 3.
Data on fetal exposure to antiretroviral agents during pregnancy are important to estimate their potential for prevention of mother-to-child transmission (PMTCT) and possible toxicity. For the recently developed HIV integrase inhibitor dolutegravir, clinical data on fetal disposition are not yet available. Dual perfusion of a single placental lobule (cotyledon) provides a useful ex vivo model to predict the in vivo maternal-to-fetal transfer of this drug. The aim of this study was to estimate the transfer of dolutegravir across the human term placenta, using a dual-perfusion cotyledon model.
After cannulation of the cotyledons (n = 6), a fetal circulation of 6 mL/min and maternal circulation of 12 mL/min were initiated. The perfusion medium consisted of Krebs-Henseleit buffer (pH = 7.2-7.4) supplemented with 10.1 mM glucose, 30 g/L human serum albumin and 0.5 mL/L heparin 5000IE. Dolutegravir was administered to the maternal circulation (∼ 4.2 mg/L) and analysed by UPLC-MS/MS.
After 3 h of perfusion, the mean ± SD fetal-to-maternal (FTM) concentration ratio of dolutegravir was 0.6 ± 0.2 and the mean ± SD concentrations in the maternal and fetal compartments were 2.3 ± 0.4 and 1.3 ± 0.3 mg/L, respectively.
Dolutegravir crosses the blood-placental barrier with a mean FTM concentration ratio of 0.6. Compared with other antiretroviral agents, placental transfer of dolutegravir is moderate to high. These data suggest that dolutegravir holds clinical potential for pre-exposure prophylaxis and consequently PMTCT, but also risk of fetal toxicity.
孕期胎儿暴露于抗逆转录病毒药物的数据对于评估其预防母婴传播（PMTCT）的潜力及可能的毒性十分重要。对于最近研发的HIV整合酶抑制剂多替拉韦，尚无关于胎儿处置的临床数据。对单个胎盘小叶（子叶）进行双重灌注可提供一个有用的体外模型，以预测该药物在体内从母体到胎儿的转运情况。本研究的目的是使用双重灌注子叶模型评估多替拉韦在足月人胎盘中的转运情况。
在对子叶进行插管（n = 6）后，启动胎儿循环6 mL/分钟和母体循环12 mL/分钟。灌注介质由克雷布斯-亨塞尔特缓冲液（pH = 7.2 - 7.4）组成，添加了10.1 mM葡萄糖、30 g/L人血清白蛋白和0.5 mL/L 5000 IE肝素。将多替拉韦给予母体循环（约4.2 mg/L），并通过超高效液相色谱-串联质谱法（UPLC-MS/MS）进行分析。
灌注3小时后，多替拉韦的平均±标准差胎儿与母体（FTM）浓度比为0.6 ± 0.2，母体和胎儿隔室中的平均±标准差浓度分别为2.3 ± 0.4和1.3 ± 0.3 mg/L。
多替拉韦可穿过血胎盘屏障，平均FTM浓度比为0.6。与其他抗逆转录病毒药物相比，多替拉韦的胎盘转运为中度至高。这些数据表明，多替拉韦在暴露前预防以及因此在PMTCT方面具有临床潜力，但也存在胎儿毒性风险。
