Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions

Zhang, Lei; Strong, John M.; Qiu, Wei; Lesko, Lawrence J.; Huang, Shiew‐Mei

doi:10.1021/mp050095h

Cited by 142 publications

(92 citation statements)

References 43 publications

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“…These data indicate that DDI caused by P-gp induction, although it remains to be proven, is possible in humans. Zhang et al (2006a) presented the position of the United States Food and Drug Administration on transporter-mediated DDI focusing particularly on P-gp. Subsequently, the United States Food and Drug Administration developed guidelines for drug transporter-mediated DDI.…”

Section: What Is the Possibility For Drug-drug Interactions Mediated mentioning

confidence: 99%

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Liu¹,

Chen²,

Smith³

2008

J Pharmacol Exp Ther

165

156

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This review discusses strategies to optimize brain penetration from the perspective of drug discovery and development. Brain penetration kinetics can be described by the extent and time to reach brain equilibrium. The extent is defined as the ratio of free brain concentration to free plasma concentration at steady state. For all central nervous system (CNS) drug discovery programs, optimization of the extent of brain penetration should focus on designing and selecting compounds having low efflux transport at the blood-brain barrier (BBB). The time to reach brain equilibrium is determined by both BBB permeability and brain tissue binding. Rapid brain penetration can be achieved by increasing passive permeability and reducing brain tissue binding. Although many drug transporters have been identified at the BBB, the available literature demonstrates only the in vivo functional importance of P-glycoprotein (P-gp) in limiting brain penetration of its substrates. Drug-drug interactions mediated by P-gp at the BBB are possible due to inhibition or induction of P-gp. For newly identified drug transporters at the BBB, more research is needed to reveal their in vivo significance. We propose the following strategies for addressing drug transporters at the BBB. 1) Drug discovery screens should be used to eliminate good P-gp substrates for CNS targets. Special consideration could be given to moderate P-gp substrates as potential CNS drugs based on a high unmet medical need and the presence of a large safety margin. 2) Selection of P-gp substrates as drug candidates for non-CNS targets can reduce their CNS-mediated side effects.Brain is separated from the systemic circulation by two barriers: the blood-brain barrier (BBB) and the blood-cerebrospinal-fluid barrier (BCSFB). The BBB is composed of cerebral endothelial cells that differ from those in the rest of the body by the presence of extensive tight junctions, absence of fenestrations, and sparse pinocytotic vesicular transport. The BCSFB is formed by a continuous layer of polarized epithelial cells that line the choroid plexus. The BBB and BCSFB exhibit very low paracellular permeability and express multiple drug transporters. These characteristics restrict the entry of hydrophilic compounds or efflux transport substrates into brain (Davson and Segal, 1995). In this review, we will summarize recent published data relevant to assess drug brain penetration and present the authors' opinions on how to effectively address BBB issues in drug discovery and development.

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Section: What Is the Possibility For Drug-drug Interactions Mediated mentioning

confidence: 99%

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Liu¹,

Chen²,

Smith³

2008

J Pharmacol Exp Ther

165

156

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“…OCT1 acts in the hepatic uptake of several prescription drugs, most notably, the antidiabetic agent metformin (3,4). Because of its multispecificity for many xenobiotics and its abundant expression in the liver, it has been proposed that the primary role of OCT1 is to work in concert with drug-metabolizing enzymes (e.g., cytochrome P450s) in detoxification pathways in the liver (5). In fact, with the exception of changes in hepatic drug disposition, Oct1 knockout mice appear healthy with no obvious phenotypic abnormalities (3,6).…”

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confidence: 99%

OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin

Chen

Shu

Liang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

206

256

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Significance This manuscript describes a previously unidentified mechanism for organic cation transporter 1 (OCT1), the major hepatic metformin transporter, in hepatic steatosis. Here we show that OCT1, long thought to function primarily as a transporter for drugs, functions as a major thiamine transporter in the liver, which has profound implications in cellular metabolism. Collectively, our results point to an important role of thiamine (through OCT1) in hepatic steatosis and suggest that the modulation of thiamine disposition by metformin may contribute to its pharmacologic effects.

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“…Transporters as well as metabolic enzymes are being increasingly recognized as a determinant of pharmacokinetics (Mizuno and Sugiyama, 2002;Mizuno et al, 2003;Zhang et al, 2006Zhang et al, , 2008. Because drug metabolism and biliary excretion occur after sinusoidal uptake of drugs in the liver, hepatic uptake transporters play an important role in hepatic clearances of drugs, even for those with a metabolism elimination pathway (Yamazaki et al, 1996;.…”

mentioning

confidence: 99%

Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats

Shitara

Nagamatsu²,

Wada³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Cyclosporin A (CsA) is a well known inhibitor of the organic aniontransporting polypeptide (OATP/Oatp) family transporters, causing a large number of transporter-mediated drug-drug interactions in clinical situations. In the present study, we examined the inhibitory effect of CsA on the hepatic uptake of sulfobromophthalein (BSP) in rats, focusing on a long-lasting inhibition. Twenty-one hours after the subcutaneous administration of CsA, the hepatic clearance of BSP was decreased. The liver uptake index study revealed that hepatic uptake of BSP was reduced in CsA-treated rats for at least 3 days. Comparison of uptake studies using isolated hepatocytes prepared from control and CsA-treated rats showed that hepatic uptake in CsA-treated rats was decreased. In primary cultured hepatocytes, after preincubation with CsA, the uptake of The inhibitory effect of CsA on the transporter-mediated uptake of BSP cannot be explained by a simple competitive mechanism and a novel mechanism should be considered.

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Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions

Cited by 142 publications

References 43 publications

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Progress in Brain Penetration Evaluation in Drug Discovery and Development

OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin

Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats

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