Transfer of repaglinide in the dually perfused human placenta and the role of organic anion transporting polypeptides (OATPs) Kristiina Tertti a,b,⇑ , Aleksanteri Petsalo c , Mikko Niemi d , Ulla Ekblad a , Ari Tolonen e , Tapani Rönnemaa f , Miia Turpeinen g , Tuija Heikkinen a , Kari Laine h,i a Department of Obstetrics and Gynecology, Turku University Central Hospital, Turku, Finland b The Joint Clinical Biochemistry Laboratory of University of Turku, Turku University Central Hospital, Turku, Finland c Department of Chemistry, University of Oulu, Oulu, Finland d Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland e Admescope Ltd, 90570 Oulu, Finland f Department of Medicine, University of Turku, Turku, Finland g Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland h Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Finland i TYKSLAB, Unit of Clinical Pharmacology, Turku, Finland article info Article history: Received 2 February 2011 Received in revised form 6 May 2011 Accepted 5 July 2011 Available online 12 July 2011 Keywords: Repaglinide Placental transfer OATPs abstract Objectives: Our aim was to investigate the placental transfer of repaglinide by ex vivo placental perfusion experiment. In addition, the involvement of the active organic anion transporters (OATP1B1, OATP1B3 and OATP2B1) was studied by assessing the single nucleotide polymorphisms (SNPs) in genes (SLCO1B1, SLCO1B3 and SLCO2B1) encoding OATPs. Study design: Fifteen placentas were obtained after delivery and a 2-h non-recirculating perfusion of a single placental cotyledon was performed to study maternal-to-fetal and fetal-to-maternal transport of repaglinide by using antipyrine as a reference of passive-diffusion transfer compound. Genotyping was performed for all placentas. Results: Maternal-to-fetal transfer of repaglinide and antipyrine were 1.5% and 13.2%, respectively, and fetal-to-maternal transfers were 6.7% and 40.3%, respectively. Fetal-to-maternal transfer of repaglinide was statistically significantly higher than maternal-to-fetal transfer (P < 0.0001). The number of placentas was not sufficient for proper statistical analysis, but the fetal-to-maternal transfer seemed to be affected by the SLCO1B3 polymorphism. Conclusions: The placental transfer of repaglinide from mother to fetus was low. Since a higher transfer rate of repaglinide was observed in fetal-to-maternal than maternal-to-fetal direction, active transport by OATP-transporters may be an important factor in fetal exposure to repaglinide. Ó 2011 Elsevier B.V. All rights reserved. 1. Introduction Repaglinide is a short acting oral hypoglycaemic agent, which has been developed for the treatment of type 2 diabetes. It lowers blood glucose concentrations by stimulating release of insulin from pancreatic beta cells (Hatorp, 2002). The information on its use during pregnancy is scarce. There are no published studies addressing the human placental transfer of repaglinide or nategli- nide, which belong to the meglitinide class of blood glucose- lowering drugs. There are three case reports of women who used repaglinide at conception and during the first 7 weeks of pregnancy. No malformations of the newborn were observed (Mol- lar-Puchades et al., 2007; Napoli et al., 2006). A pre-clinical repro- duction study in rats showed that repaglinide may affect fetal growth but is not teratogenic (Viertel and Guttner, 2000). Most small-molecular weight agents cross the placenta princi- pally by diffusion (Syme et al., 2004). In addition to passive trans- fer, drugs are transferred across the placenta by active transport mechanisms, by specific transporters (Mölsä et al., 2005). The pharmacokinetics of repaglinide is regulated by organic anion transporting polypeptide 1B1 (OATP1B1) function in the liver (Niemi et al., 2005). It has also been shown that repaglinide is a sig- nificant inhibitor of OATP2B1 and OATP1B3 (Bachmakov et al., 2008). Organic anion transporting proteins are also expressed in placenta. OATP2B1 functions as an uptake transporter in the fetal 0928-0987/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2011.07.002 ⇑ Corresponding author at: Department of Obstetrics and Gynecology, Turku University Central Hospital, Kiinamyllynkatu 4-8, FIN-20521 Turku, Finland. Tel.: +358 50 3772747. E-mail address: kristiina.tertti@tyks.fi (K. Tertti). European Journal of Pharmaceutical Sciences 44 (2011) 181–186 Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps