Pharmacogenetics of Drug Transporters

Schwabedissen, Henriette E. Meyer zu; Grube, Markus; Kroemer, Heyo K.

doi:10.1002/9781118116494.ch4

Cited by 4 publications

(3 citation statements)

References 318 publications

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“…Therefore, while further studies are warranted, we speculate that for other compounds and those tested here, addition of biguanide functionality may be able to provide an efficient excretion route in vivo via the MATE expressed in the kidney and liver, as has been shown for other OCT substrates and biguanides. [47][48][49] To conclude, we have demonstrated that addition of a biguanide functional group to structurally diverse transporter-impermeable compounds enhances their OCT-mediated transport (Figure 8). Physicochemical properties, especially accessible surface area, molecular weight, and volume, correlate with the uptake of biguanides by OCT2, but not OCT1.…”

Section: Discussionmentioning

confidence: 73%

Incorporation of a Biguanide Scaffold Enhances Drug Uptake by Organic Cation Transporters 1 and 2

Obianom¹

2016

Preprint

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Membrane transporters play a significant role in the transport of many endogenous and exogenous compounds. The knowledge of transporter substrate requirements has allowed further development of drugs that utilize them to ensure tissue permeation. In this study, we demonstrate that inclusion of a biguanide functionality can potentiate uptake by the organic cation transporters 1 and 2 (OCT1 and OCT2). We synthesized 18 pairs of structurally diverse compounds, each pair consisting of a parent amino compound and its biguanide analog; and then assessed their cellular uptake in HEK293 cells overexpressing human OCT1 or OCT2. Our results show that addition of the biguanide significantly improved OCT1-and OCT2-mediated transport for the majority of compounds. The biguanides also inhibited the uptake of prototypical substrates of both transporters, 1-methyl-4-phenylpyridinium (MPP + ) and metformin. We found that molecular weight, molecular volume, Log D (pH 7.4), and accessible surface area were important determinants of OCT2 substrates, but none of these parameters was a significant factor for OCT1. More so, the inhibition of MPP + uptake correlated linearly with that of metformin uptake for the tested biguanides in both cell lines. Taken together, we conclude that the inclusion of the biguanide scaffold in nonsubstrates of OCT1 and OCT2 increase their propensity to become substrates and inhibitors for these transporters.

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Section: Discussionmentioning

confidence: 73%

Incorporation of a Biguanide Scaffold Enhances Drug Uptake by Organic Cation Transporters 1 and 2

Obianom¹

2016

Preprint

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“…Even if several functional genetic variants of OATP1B3 have been identified (33)(34)(35), the role of this transporter in vivo is rather unknown. This may be explained by the fact that the genetic variants in SLCO1B3 with severely reduced transport function are rare, and common nonsynonymous variants show only moderate functional impairment in vitro (22,37). In addition, there is broad substrate overlap between OATP1B3 and OATP1B1, with the latter exhibiting higher affinity to most of the thus far identified substrate drugs in clinical use (38).…”

Section: Discussionmentioning

confidence: 99%

OATP1B3 Is Expressed in Pancreatic β-Islet Cells and Enhances the Insulinotropic Effect of the Sulfonylurea Derivative Glibenclamide

et al. 2014

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Organic anion transporting polypeptide OATP1B3 is a membrane-bound drug transporter that facilitates cellular entry of a variety of substrates. Most of the previous studies focused on its hepatic expression and function in hepatic drug elimination. In this study, we report expression of OATP1B3 in human pancreatic tissue, with the abundance of the transporter localized in the islets of Langerhans. Transport studies using OATP1B3-overexpressing MDCKII cells revealed significant inhibition of the cellular uptake of the known substrate cholecystokinin-8 in the presence of the insulinotropic antidiabetes compounds tolbutamide, glibenclamide, glimepiride, and nateglinide and identified glibenclamide as a novel substrate of OATP1B3. Sulfonylurea derivatives exert their insulinotropic effect by binding to the SUR1 subunit of the KATP channels inducing insulin secretion in β-cells. Here, we show that transient overexpression of human OATP1B3 in a murine β-cell line (MIN6)—which exhibits glucose and glibenclamide-sensitive insulin secretion—significantly enhances the insulinotropic effect of glibenclamide without affecting glucose-stimulated insulin secretion. Taken together, our data provide evidence that the drug transporter OATP1B3 functions as a determinant of the insulinotropic effect of glibenclamide on the tissue level. Changes in transport activity based on drug-drug interactions or genetic variability may therefore influence glibenclamide efficacy.

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“…Both have been shown to be involved in the hepatic uptake of various drugs thereby influencing their systemic exposure. Importantly, the certainty in evaluating their clinical relevance is clearly driven by the fact that frequently occurring genetic loss-of-function variants exist, allowing in vivo comparisons for the impact of these transporters, which are mainly expressed in the liver [17][18][19][20]. In addition to the OATP1B-transporters, OATP1A2 and OATP2B1 have also been shown to interact with numerous drugs [21]; however, these findings are mainly from in vitro experiments and have so far only been validated to a very limited extent in vivo.…”

Section: Oatp/slco Transportermentioning

confidence: 99%

Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

2021

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The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

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Pharmacogenetics of Drug Transporters

Cited by 4 publications

References 318 publications

Incorporation of a Biguanide Scaffold Enhances Drug Uptake by Organic Cation Transporters 1 and 2

Incorporation of a Biguanide Scaffold Enhances Drug Uptake by Organic Cation Transporters 1 and 2

OATP1B3 Is Expressed in Pancreatic β-Islet Cells and Enhances the Insulinotropic Effect of the Sulfonylurea Derivative Glibenclamide

Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

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