Treatment of gestational diabetes mellitus; importance of placental drug transporters

Gestational diabetes mellitus (GDM) is defined as ‘any degree of glucose intolerance with onset or first recognition during pregnancy’ that complicates gestation and presents a risk of long-term diabetes in both the mother and offspring (Ben-Haroush et al., 2004). GDM develops in about 5% of pregnant women with increasing prevalence; it is assumed these figures may reach up to 20%, mostly in obese women (Gauster et al., 2012). The management of GDM consists mainly of diet and lifestyle modification; when these approaches fail to restore normoglycemia, insulin is the drug of choice. However, insulin treatment has been associated with several limitations, such as immune response, hypoglycemia, weight gain, as well as the need to educate the patient. In addition, pain and discomfort connected with insulin administration complicate the treatment and may lead to non-compliance (Gedeon and Koren, 2006). Low-molecular oral hypoglycemic agents are, therefore, still searched for as a “more comfortable” alternative and, indeed, recent evidence based on trials and meta-analyses shows that GDM can be safely and effectively treated with oral hypoglycemic agents such as glyburide or metformin (Rowan et al., 2008; Nicholson et al., 2009; Waugh et al., 2010; Renda et al., 2011). Both of these agents are recognized substrates of various drug transporters (see Tables 1 and 2) and their materno-fetal transport is, therefore, largely controlled by levels of expression of placental transporters.

Glyburide (also known as glibenclamide), a second generation sulfonylurea agent that increases secretion of endogenous insulin, appears to be a good candidate for GDM treatment (Coustan, 2007) as it only insignificantly crosses the human placenta (Elliott et al., 1991; Elliott et al., 1994; Langer et al., 2000). The low transplacental permeability of glyburide was originally attributed to very extensive plasma protein binding coupled with a short elimination half-life (Koren, 2001; Nanovskaya et al., 2006a). However, using in vitro perfusions of a human placental cotyledon, Kraemer et al., (2006) observed that glyburide was actively transported from fetus to mother by a transporter other than P-glycoprotein (Kraemer et al., 2006). Shortly afterwards, the involvement of BCRP in the active efflux of glyburide in the feto-maternal direction was identified using in vitro brush border human placental vesicles (Gedeon et al., 2008), ex vivo perfusion of human placental cotyledons (Pollex et al., 2008) and in vivo in the Bcrp1(-/-) pregnant mice (Zhou et al., 2008). We further demonstrated the ability of placental BCRP not only to hinder the maternal-to-fetal penetration of glyburide, but even to accelerate the feto-maternal transport of glyburide in a concentration-dependent manner (Cygalova et al., 2009). Glyburide, thus, seems to posses ideal pharmacokinetic properties (i.e. affinity to drug efflux transporter, high plasma protein binding and short elimination half-life) that preclude its transplacental transport.

Metformin, a biguanide derivative, has for long been considered to be non-teratogenic (Coetzee and Jackson, 1979; Coetzee and Jackson, 1984; Coetzee and Jackson, 1985); however, the recommendation for the use of metformin in pregnancy was introduced without proper knowledge of its transplacental passage and effects on fetus. In a recent randomized controlled open trial of 751 women with gestational diabetes, Rowan et al., (2008) evaluated the efficiency and safety of insulin versus metformin treatment. Comparing outcomes such as maternal and neonatal hypoglycemia, respiratory distress, birth trauma, Apgar score, prematurity, neonatal anthropomorphic measurements, postpartum glucose tolerance, and acceptability of treatment the authors reported no significant differences between the metformin and insulin groups. In addition, the women preferred metformin treatment to insulin (Rowan et al., 2008).

Regarding metformin affinity to drug transporters, this compound is a well-recognized substrate of many SLC proteins, including influx OCT1, OCT2 and OCT3 and efflux MATE1 and MATE2 transporters (Table 2). Considering functional expression of OCT1 and OCT3 in the human placenta, their role in transplacental pharmacokinetics of metformin can be expected. Several research groups used dually perfused ex vivo placental cotyledon model to study transport of metformin across the placenta, however, with differing results. Kovo et al., (2008a) reported that the transplacental clearance index for metformin was quite low (0.34 ± 0.05) (Kovo et al., 2008a) and only slightly higher than that of glyburide (0.21 ± 0.09) (Elliott et al., 1994). Subsequently the same team suggested that metformin permeability across the placenta is mediated by a carrier transporting cationic compounds bi-directionally, with a higher transfer rate from the fetal to the maternal side (Kovo et al., 2008b). On the other hand, other teams reported on fast transplacental passage of metformin from mother to fetus without transporter involvement (Nanovskaya et al., 2006b; Tertti et al., 2010). Unfortunately, all these studies failed to investigate dose-dependent pharmacokinetics of metformin passage across the placenta, which is an essential approach to reveal transporter-mediated and saturable process. In addition, none of these reports considered a second transporter for vectorial movement across the placenta; as discussed previously, OCTs can only uptake their substrates into the cells but another transporter is responsible for drug efflux (Figures 3 and 4). In the rat placenta, we demonstrated that metformin is transported from fetus to mother by Oct3/Mate1 vectorial transport (Ahmadimoghaddam and Staud, unpublished data). In addition, Hemauer et al., (2010) suggested the transport of metformin might be affected by P-glycoprotein and BCRP transporters in the placental brush border vesicles (Hemauer et al., 2010). However, further studies are needed to confirm the efflux of metformin from the trophoblast cells to mother.