Interaction of Thiazolidinediones (Glitazones) with the ATP-Binding Cassette Transporters P-Glycoprotein and Breast Cancer Resistance Protein

Abstract

Aims: Thiazolidinediones (glitazones) are frequently prescribed antidiabetic drugs commonly used in combination drug regimens. To evaluate the risk of drug-drug interactions, we therefore aimed to systematically investigate the inhibitory and inductive effects of all glitazones on 2 of the most relevant drug transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in vitro. Methods: The inhibition of P-gp and BCRP was assessed by fluorometric assays quantifying the increase in the intracellular concentration of fluorescent P-gp or BCRP substrates caused by their combination with the glitazones. The induction of mRNA expression was quantified by real-time RT-PCR after the treatment of HuH-7 cells with the respective compounds for 4 days. Results: Rosiglitazone and troglitazone significantly inhibited P-gp and BCRP function and induced mRNA expression of BCRP but not of P-gp. Pioglitazone, which exhibited very low solubility, could only be tested up to 0.5 μmol/l and did not provoke an effect in any of the assays. Conclusions: After comparison of the in vitro data and published clinical studies, it seems unlikely that the inhibition of BCRP and P-gp by rosiglitazone plays a role in the clinical situation. In contrast, BCRP induction by rosiglitazone might be of relevance in vivo, but has to be verified in dedicated clinical studies.

Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice

“…Abcc1, 2, 4, and Abcg2 mRNA and/or protein expression was increased in liver, which is consistent with what was observed in livers of T2DM rats [49]. Abcc1 and Abcg2, along with Abcb1, can transport the antidiabetic drug rosiglitazone [50]. Severe liver injury has been reported in a person with T2DM [51] and cholestatic injury has also been observed after rosiglitazone therapy [52] – both suggesting hepatic clearance is necessary.…”

Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's disease

“…Our findings are comparable to another study that investigated the involvement of transporters at the human placental apical membrane on the penetration of rosiglitazone, a close structural analogue of pioglitazone. Having investigated effects of three drug efflux transporters (P-gp, BCRP and Multidrug Resistance Protein, MRP1) at the human placental apical membrane, Weiss et al also found that rosiglitazone was predominantly transported by P-gp24. We noted a small rise from 16.92 to 20.82% in the brain-plasma ratios after treatment with the P-gp inhibitor or P-gp + BCRP inhibitors.…”

“…At present, no study has successfully addressed this factor. Therefore, in this study, we investigated the two most relevant drug efflux transporters, P-gp and breast cancer resistance protein (BCRP)24, as potential barriers to brain penetration of pioglitazone. Our in vivo experiments demonstrate that inhibition of P-gp leads to a significant although not substantial increase in the levels of pioglitazone in brain tissue, indicating the involvement of P-gp in limiting pioglitazone brain penetration.…”

Modulation of glucose metabolism by a natural compound from Chloranthus japonicus via activation of AMP-activated protein kinase

“…The function of AMPK in regulating glucose metabolism has been demonstrated with several AMPK activators, such as metformin and AICAR, to increase AMPKa phosphorylation and mediates glucose metabolisms both in vivo and in vitro 9, 10 . Thiazolidinedione (TZDs) up-regulates the cellular AMP/ATP ratio, which in turn activates AMPK activation and suppresses gluconeogenesis 11 .…”