Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

Abstract

Abstract. Glyburide (glibenclamide, GLB) is a widely prescribed antidiabetic with potential beneficial effects in central nervous system injury and diseases. In vitro studies show that GLB is a substrate of organic anion transporting polypeptide (OATP) and ATP-binding cassette (ABC) transporter families, which may influence GLB distribution and pharmacokinetics in vivo. In the present study, we used [11 C] GLB positron emission tomography (PET) imaging to non-invasively observe the distribution of GLB at a non-saturating tracer dose in baboons. The role of OATP and P-glycoprotein (P-gp) in [11 C]GLB whole-body distribution, plasma kinetics, and metabolism was assessed using the OATP inhibitor rifampicin and the dual OATP/P-gp inhibitor cyclosporine. Finally, we used in situ brain perfusion in mice to pinpoint the effect of ABC transporters on GLB transport at the blood-brain barrier (BBB). PET revealed the critical role of OATP on liver [ 11 C]GLB uptake and its subsequent impact on [11 C]GLB metabolism and plasma clearance. OATP-mediated uptake also occurred in the myocardium and kidney parenchyma but not the brain. The inhibition of P-gp in addition to OATP did not further influence [11 C] GLB tissue and plasma kinetics. At the BBB, the inhibition of both P-gp and breast cancer resistance protein (BCRP) was necessary to demonstrate the role of ABC transporters in limiting GLB brain uptake. This study demonstrates that GLB distribution, metabolism, and elimination are greatly dependent on OATP activity, the first step in GLB hepatic clearance. Conversely, P-gp, BCRP, and probably multidrug resistance protein 4 work in synergy to limit GLB brain uptake.

Pharmacoepidemiologic and in vitro evaluation of potential drug–drug interactions of sulfonylureas with fibrates and statins

“…Future studies using a more physiologically relevant system, including both human liver and intestinal microsomes, may provide a better understanding on the effects of fenofibrate and gemfibrozil on the metabolism of glyburide. Interactions of glyburide with fenofibrate, gemfibrozil and simvastatin could also occur at the level of organic anion transporter polypeptides (OATPs) which have been suggested to play an important role in the pharmacokinetics of glyburide [31,32]. Glyburide is a substrate of OATP2B1 [33] and was able to inhibit OATP1B1-mediated uptake of pitavastatin in vitro [34], suggesting that it may also be a substrate of OATP1B1.…”

Imaging the impact of cyclosporin A and dipyridamole on P-glycoprotein (ABCB1) function at the blood-brain barrier: A [11C]-N-desmethyl-loperamide PET study in nonhuman primates

“…CsA was infused for 30 min before and during the whole following PET experiment as previously described (Tournier et al, 2013).…”

“…[ 11 C]dLop baseline brain distribution was found to be low and highly sensitive to P-gp (Tournier et al, 2013). Brain distribution of [ 11 C]dLop in the presence of CsA was not homogeneous and was shown to be influenced by the regional blood-flow (Liow et al, 2009).…”

Dysregulation of solute carrier transporters in malaria‐infected pregnant mice

“…This is especially relevant as there is a higher incidence of malaria in HIV‐infected women, and the geographic distribution of areas with high infection rates of malaria and HIV tend to overlap, resulting in significant risk of co‐infection . Next, OATP2B1 and BCRP are highly expressed in the placenta and evidence suggests that they are jointly involved in transplacental transfer of endogenous bile acids and steroid hormones as well as clinically relevant drugs such as statins and glyburide . We observed that Oatp2b1 and Bcrp were both significantly downregulated in placenta following PbA infection regardless of L‐arginine supplementation.…”