Testing Pharmacokinetics and Efficacy of Pravastatin Using Feto-Maternal Interface Organ-On-Chips

Pravastatin reduce pro-inflammatory mediators in feto-maternal interface (FMi) tissues and minimize PE-like symptoms vitro animal models. Several questions remain regarding the drug’s pharmacokinetics (PK), metabolism, efficacy that cannot be fully answered using traditional 2D cell culture or placental perfusion models prior to clinical trials. We used two distinct microfluidic organ-on-chip (OOC) are interconnected through microchannels maintain intercellular interactions between cells faithfully represents human FMi test pravastatin’s PK cellular responses at fetal membranes (FM) placenta (P). Two OOC’s for these studies were: 1) FM-OOC containing four concentric circular chambers (decidua; chorion trophoblasts, amnion [mesenchyme epithelium]) collagen matrix. 2) P-OOC comprised of three rectangular syncytiotrophoblasts (Syn), cytotrophoblasts, HUVEC (Fig 1A). (200 ng/mL) was applied decidua SYN chamber under normal oxidative stress (OS) conditions mimic maternal drug exposure during PE. determined metabolism (LC-MS/MS) its (cytokine assay) over 24 hours (h). traversed both FM P OOCs 4h documenting 1A) produced unique pravastatin metabolites a time, cell, organ dependent manner. Desacyl-dehydropravastain found all layers within (P < 0.05). isomer metabolite only by 0.05) 1B). OS treatment induced environment (P<0.05), which reversed (increased anti-inflammatory cytokines [IL-10/IL-4]) 2). Our study showed, first membrane-decidual plays vital role transport, Pravastatin. This project provided data needed preclinical trials preterm birth PE.View Large Image Figure ViewerDownload Hi-res image Download (PPT)