Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Active transport across biological membranes has become a noticeable factor in the absorption, distribution, and excretion of an increasing number of drugs. Different transmembrane transport systems including organic anion transporters (OATP, solute carrier family SLC21A), organic cation transporters (OCT, SLC22A), dipeptide transporters (PEPT, SLC15A), nucleoside transporters (CNT, SLC28A), monocarboxylate carriers (MCT, SLC2A), and members of the large ATP-binding cassette family (ABC, SLC3A) are involved in drug disposition. Genetic polymorphisms in transport proteins frequently occur and contribute to interindividual differences in the efficacy and safety of pharmatherapy. Currently, the most advanced research has been done on P-glycoprotein (ABCB1, SLC3A1.201.1). Knowledge of this transporter indicates that haplotype analysis rather than association with single nucleotide polymorphisms (SNPs) provides the most appropriate interpretation of pharmacogenetic data from drug transporters. This review gives an overview and update on the pharmacological impact of genetic variants in transmembrane transporters.
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PMID:Impact of genetic polymorphisms in transmembrane carrier-systems on drug and xenobiotic distribution. 1459 19

The brain uptake of xenobiotics is restricted by the blood-brain brain barrier formed by brain capillary endothelial cells. Active efflux transport systems in the blood-brain barrier work as a detoxification system in the brain by facilitating removal of xenobiotic compounds from the brain. Drugs, acting in the brain, have to overcome such efflux mechanisms to achieve clinically significant concentration in the brain. Multiple transporters are involved in this efflux transport in the brain capillaries. In the past few years, considerable progress has been made in the cloning of these transporters and their functional characterization after heterologous expression. Members of the solute carrier family (SLC) play an important role in the efflux transport, especially for organic anions, which include organic anion transporting polypeptides (OATP/SLCO) and organic anion transporters (OAT/SLC22A). It is believed that coordination of the members of SLC family, and ABC transporters, such as P-glycoprotein, multidrug resistance protein, and breast cancer-resistant protein (BCRP/ABCG2), allows an efficient vectorial transport across the endothelial cells to remove xenobiotics from the brain. In this review, we shall summarize our current knowledge about their localization, molecular and functional characteristics, and substrate and inhibitor specificity.
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PMID:Active efflux across the blood-brain barrier: role of the solute carrier family. 1571 59

The purpose of this study was to gain a better understanding of the transport mechanism of pitavastatin, a novel synthetic HMG-CoA reductase inhibitor. Experiments were performed using oocytes of Xenopus laevis expressing several solute carrier (SLC) transporters and recombinant membrane vesicles expressing several human ABC transporters. The acid form of pitavastatin was shown to be a substrate for human OATP1, OATP2, OATP8, OAT3 and NTCP, and for rat Oatp1 and Oatp4 with relatively low K(m) values. In contrast, these SLC transporters were not involved in the uptake of the lactone form. A significant stimulatory effect was exhibited by pitavastatin lactone, while the acid form did not exhibit ATPase hydrolysis of P-glycoprotein. In the case of breast cancer resistant protein (BCRP), the acid form of pitavastatin is a substrate, whereas the lactone form is not. Taking these results into consideration, several SLC and ABC transporters were identified as critical to the distribution and excretion of pitavastatin in the body. This study showed, for the first time, that acid and lactone forms of pitavastatin differ in substrate activity towards uptake and efflux transporters. These results will potentially contribute to the differences in the pharmacokinetic profiles of pitavastatin.
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PMID:Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. 1625 59

Drug transporters are increasingly recognized as a key determinant of drug disposition and response. It is now widely appreciated that expression of the ATP-dependent efflux transporter, MDR1 (ABCB1, P-glycoprotein), in organs such as the gastrointestinal tract, liver and kidney significantly alters the extent of drug absorption and excretion. Moreover, expression of MDR1 at the level of the blood-brain barrier limits the entry of many drugs into the central nervous system. Given such an important role of MDR1 in the drug disposition process, it is not surprising to see increasing focus on the role of single nucleotide polymorphisms (SNPs) in this transporter as a potential determinant of interindividual variability in drug disposition and pharmacological response. However, drug transport is often the result of the concerted action of efflux and uptake pumps located both in the basolateral and apical membranes of epithelial cells. A growing list of membrane-spanning proteins involved in the in- or outward transport of a large variety of drugs has been recognized and characterized over the past few years in almost all tissues, including organic anion and cation transporters (OAT, OCT, solute carrier family SLC22A), organic anion transport proteins (OATP, solute carrier family SLCO, formerly SLC21A), and MRPs (ABCCs), other members of the ATP-binding cassette family. We are just beginning to appreciate their role for drug delivery and disposition and the contribution of genetic polymorphisms in these transport proteins to interindividual variability in the efficacy and safety for pharmacotherapy. This review summarizes the consequences of inherited differences in drug transport for pharmacotherapy. With the main focus on ABCB1, an update of recent advances is given and clinically relevant examples are used to illustrate how heritable differential drug transport can help to explain individual variability in drug response. The pharmacogenetics of other transporters is briefly introduced.
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PMID:Implications of genetic polymorphisms in drug transporters for pharmacotherapy. 1650 81

Inter-individual variability in drug response and the emergence of adverse drug reactions are main causes of treatment failure in cancer therapy. Recently, membrane transporters have been recognized as an important determinant of drug disposition, thereby affecting chemosensitivity and -resistance. Genetic factors contribute to inter-individual variability in drug transport and targeting. Therefore, pharmacogenetic studies of membrane transporters can lead to new approaches for optimizing cancer therapy. This review discusses genetic variations in efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (MDR1, P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2 (BCRP), and uptake transporters of the solute carrier (SLC) family such as SLC19A1 (RFC1) and SLCO1B1 (SLC21A6), and their relevance to cancer chemotherapy. Furthermore, a pharmacogenomic approach is outlined, which using correlations between the growth inhibitory potency of anticancer drugs and transporter gene expression in multiple human cancer cell lines, has shown promise for determining the relevant transporters for any given drugs and predicting anticancer drug response.
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PMID:Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy. 1732 26

Transporters govern drug movement into and out of tissues, thereby playing an important role in drug disposition in plasma and to the site of action. The molecular cloning of such transporters has clarified the importance of members of the solute carrier family, such as OATP/SLCO, OCT/SLC22, OAT/SLC22, and MATE/SLC47, and the ATP-binding cassette transporters, such as P-glycoprotein/ABCB1, MRPs/ABCC, and BCRP/ABCG2. Elucidation of molecular characteristics of transporters has allowed the identification of transporters as mechanisms for drug-drug interactions, and of interindividual differences in drug dispositions and responses. Cumulative studies have highlighted the cooperative roles of uptake transporters and metabolic enzymes/efflux transporters. In this way, the concept of a rate-limiting process in hepatic/renal elimination across epithelial cells has developed. This review illustrates the concept of the rate-limiting step in the hepatic elimination mediated by transporters, and describes the prediction of the in vivo pharmacokinetics of drugs whose disposition is determined by transporters, based on in vitro experiments using pravastatin as an example. This review also illustrates the transporters regulating the peripheral drug concentrations.
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PMID:In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. 1925 35

The colon provides a plethora of therapeutic opportunities. There are multiple disease targets, drug molecules, and colon-specific delivery systems to be explored. Clinical studies highlight the potential for systemic delivery via the colon, and the emerging data on the levels of cell membrane transporters and metabolic enzymes along the gut could prove advantageous for this. Often efflux transporters and metabolic enzyme levels are lower in the colon, suggesting a potential for improved bioavailability of drug substrates at this site. The locoregional distribution of multiple metabolic enzymes (including cytochromes), efflux transporters (including P-glycoprotein and breast cancer resistance proteins), and influx transporters (including the solute carrier family) along the intestine is summarized. Local delivery to the colonic mucosa remains a valuable therapeutic option. New therapies that target inflammatory mediators could improve the treatment of inflammatory bowel disease, and old and new anticancer molecules could, when delivered topically, prove to be beneficial adjuncts to the current systemic or surgical treatments. New issues such as pharmacogenomics, chronotherapeutics, and the delivery of prebiotics and probiotics are also discussed in this review. Targeting drugs to the colon utilizes various strategies, each with their advantages and flaws. The most promising systems are considered in the light of the physiological data which influence their in vivo behavior.
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PMID:Colonic treatments and targets: issues and opportunities. 1955 65

Drug resistance was first identified in cancer cells that express proteins known as multidrug resistance proteins that extrude the therapeutic agents out of the cells resulting in alteration of pharmacokinetics, tissue distribution, and pharmacodynamics of drugs. To this end studies were carried out to investigate the role of pharmacological inhibitors and pharmaceutical excipients with a primary focus on P-glycoprotein (P-gp). The aim of this study was to investigate holistic changes in transporter gene expression during permeability upon formulation of indomethacin as solid dispersion. Initial characterization studies of solid dispersion of indomethacin showed that the drug was dispersed within the carrier in amorphous form. Analysis of permeability data across Caco-2 monolayers revealed that drug absorption increased by 4-fold when reformulated as solid dispersion. The last phase of the work involved investigation of gene expression changes of transporter genes during permeability. The results showed that there were significant differences in the expression of both ATP-binding cassette (ABC) transporter genes as well as solute carrier transporter (SLC) genes suggesting that the inclusion of polyethylene glycol as well as changes in molecular form of drug from crystalline to amorphous have a significant bearing on the expression of transporter network genes resulting in differences in drug permeability.
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PMID:Genomic evaluation during permeability of indomethacin and its solid dispersion. 2108 Jul 58

Macrophages represent major cellular targets of various drugs, especially antibiotics and anti-viral drugs. Factors that may govern intracellular accumulation of drugs in these cells, especially those related to activity of drug transporters, are consequently likely important to consider. The present study was therefore designed to extensively characterize expression of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in primary human macrophages generated from blood monocytes. Using quantitative polymerase chain reaction assays, these cells were found to exhibit very high or high levels of mRNA expression of concentrative nucleoside transporter (CNT) 3, equilibrative nucleoside transporter 3, monocarboxylate transporter (MCT) 1, MCT4, peptide/histidine transporter (PHT) 1, PHT2, organic anion transporting polypeptide transporter 2B1 and ABC pumps multidrug resistance protein (MRP) 1/ABCC1 and MRP3/ABCC3. By contrast, other transporters, including the efflux pump ABCB1/P-glycoprotein, were found at lower levels or were not expressed. Concomitantly, human macrophages displayed notable uptake of the MCT substrate lactate and of the CNT substrate uridine and also exhibited cellular efflux of the MRP substrate carboxy-2',7'-dichlorofluorescein. Such a functional expression of these transporters has likely to be considered with respect to cellular pharmacokinetics of drugs targeting macrophages.
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PMID:Drug transporter expression in human macrophages. 2121 Aug 49

Cynomolgus monkey has been used as a model for the prediction of drug disposition in human brain. The purpose of this study was to clarify protein expression levels of membrane proteins affecting drug distribution to brain, such as transporters, receptors, and junctional proteins, in cynomolgus monkey brain microvessels by using liquid chromatography tandem mass spectrometry. In adult monkeys, three ATP-binding cassette transporters (multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 4 (MRP4)), six solute carrier transporters (glucose transporter 1 (GLUT1), GLUT3/14, monocarboxylate transporter 1 (MCT1), MCT8, organic anion transporting polypeptide 1A2, and equilibrative nucleoside transporter 1), two junctional proteins (claudin-5 and vascular endothelial cadherin), and two receptors (insulin receptor and low-density lipoprotein receptor-related protein 1) were detected. Comparison of the expression levels with those in mouse, which we reported previously, revealed a pronounced species difference. BCRP expression in monkey was greater by 3.52-fold than that in mouse, whereas MDR1 and MRP4 expression levels in monkey were lower by 0.304- and 0.180-fold, respectively, than that in mouse. This study also investigated the developmental changes in expression of membrane proteins in neonate and child monkeys. Expression of MDR1 was similar in neonate and adult monkeys, whereas in rat, P-glycoprotein expression was reported to be significantly lower in brain microvessels of neonate as compared with adult rat. These results will be helpful to understand and predict brain concentrations of drugs in different species and at different ages of primates.
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PMID:Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys. 2125 69


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