Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in ...physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.
Metformin, widely used as first-line treatment for type 2 diabetes, exists primarily as a hydrophilic cation at physiological pHs. As such, membrane transporters play a substantial role in its ...absorption, tissues distribution, and renal elimination. Multiple organic cation transporters are determinants of the pharmacokinetics of metformin, and many of them are important in its pharmacological action, as mediators of metformin entry into target tissues. Furthermore, a recent genome-wide association study in a large multi-ethnic population implicated polymorphisms in SLC2A2, encoding the glucose transporter, GLUT2, as important determinants of response to metformin. Here, we describe the key transporters associated with metformin pharmacokinetics and response.
Renal transporters in drug development Morrissey, Kari M; Stocker, Sophie L; Wittwer, Matthias B ...
Annual review of pharmacology and toxicology,
01/2013, Letnik:
53
Journal Article
Recenzirano
Odprti dostop
The kidney plays a vital role in the body's defense against potentially toxic xenobiotics and metabolic waste products through elimination pathways. In particular, secretory transporters in the ...proximal tubule are major determinants of the disposition of xenobiotics, including many prescription drugs. In the past decade, considerable progress has been made in understanding the impact of renal transporters on the disposition of many clinically used drugs. In addition, renal transporters have been implicated as sites for numerous clinically important drug-drug interactions. This review begins with a description of renal drug handling and presents relevant equations for the calculation of renal clearance, including filtration and secretory clearance. In addition, data on the localization, expression, substrates, and inhibitors of renal drug transporters are tabulated. The recent US Food and Drug Administration drug-drug interaction draft guidance as it pertains to the study of renal drug transporters is presented. Renal drug elimination in special populations and transporter splicing variants are also described.
Drug transporters can govern the absorption, distribution, metabolism, and excretion of substrate drugs and endogenous substances. Investigations to examine their potential impact to pharmacokinetic ...(PK) drug‐drug interactions (DDIs) are an integral part of the risk assessment in drug development. To evaluate a new molecular entity as a potential perpetrator of transporters, use of well characterized and/or clinically relevant probe substrates with good selectivity and sensitivity are critical for robust clinical DDI assessment that could inform DDI management strategy in the product labeling. The availability of endogenous biomarkers to monitor transporter‐mediated DDIs in early phases of clinical investigations would greatly benefit downstream clinical plans. This article reviews the state‐of‐the‐art in transporter clinical probe drugs and emerging biomarkers, including current challenges and limitations, delineates methods and workflows to identify and validate novel endogenous biomarkers to support clinical DDI evaluations, and proposes how these probe drugs or biomarkers could be used in drug development.
The drug-drug interaction (DDI) potential of tyrosine kinase inhibitors (TKI) as interacting drugs via transporter inhibition has not been fully assessed. Here, we estimated the half maximal ...inhibitory concentration (IC(50)) values for 8 small-molecule TKIs (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib) on (14)Cmetformin transport by human organic cation transporters (OCT), OCT1, OCT2, and OCT3, and multidrug and toxic compound extrusion (MATE) proteins, MATE1 and MATE2-K, using human embryonic kidney cells stably expressing these transporters. We then compared the estimated IC(50) values to the maximum clinical concentrations of unbound TKIs in plasma (unbound C(max,sys,p)). Results showed that imatinib, nilotinib, gefitinib, and erlotinib exerted selectively potent inhibitory effects, with unbound C(max,sys,p)/IC(50) values ≥0.1, on MATE1, OCT3, MATE2-K, and OCT1, respectively. In comparison to the common form of OCT1, the OCT1 polymorphism, M420del, was more sensitive to drug inhibition by erlotinib. Major metabolites of several TKIs showed IC(50) values similar to those for unchanged TKIs. Taken together, these findings suggest the potential of clinical transporter-mediated DDIs between specific TKIs and OCTs and MATEs, which may affect the disposition, efficacy, and toxicity of metformin and other drugs that are substrates of these transporters. The study provides the basis for further clinical DDI studies with TKIs.
Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual ...variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value <1x10-30). In cells over-expressing human or various mammalian orthologs of SLC22A24, we showed that steroid conjugates and bile acids were substrates of the transporter. Phylogenetic, genomic, and transcriptomic analyses suggested that SLC22A24 has a specialized role in the kidney and appears to function in the reabsorption of organic anions, and in particular, anionic steroids. Phenome-wide analysis showed that functional variants of SLC22A24 are associated with human disease such as cardiovascular diseases and acne, which have been linked to dysregulated steroid metabolism. Collectively, these functional genomic studies reveal a previously uncharacterized protein involved in steroid homeostasis, opening up new possibilities for SLC22A24 as a pharmacological target for regulating steroid levels.
This white paper provides updated International Transporter Consortium (ITC) recommendations on transporters that are important in drug development following the 3rd ITC workshop. New additions ...include prospective evaluation of organic cation transporter 1 (OCT1) and retrospective evaluation of organic anion transporting polypeptide (OATP)2B1 because of their important roles in drug absorption, disposition, and effects. For the first time, the ITC underscores the importance of transporters involved in drug‐induced vitamin deficiency (THTR2) and those involved in the disposition of biomarkers of organ function (OAT2 and bile acid transporters).
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