155 research outputs found
Oral drug delivery utilizing intestinal OATP transporters
Transporters play important roles in tissue distribution and urinary- and biliary-excretion of drugs and transporter molecules involved in those processes have been elucidated well. Furthermore, an involvement of efflux transporters such as P-glycoproteins, multidrug resistance associated protein 2, and breast cancer resistance protein as the intestinal absorption barrier and/or intestinal luminal secretion mechanisms has been demonstrated. However, although there are many suggestions for the contribution of uptake/influx transporters in intestinal absorption of drugs, information on the transporter molecules responsible for the intestinal absorptive process is limited. Among them, most studied absorptive drug transporter is peptide transporter PEPT1. However, utilization of PEPT1 for oral delivery of drugs may not be high due to the chemical structural requirement of PEPT1 limited to peptide-mimetics. Recently, organic anion transporting polypeptide (OATP) family such as OATP1A2 and OATP2B1 has been suggested to mediate intestinal absorption of several drugs. Since OATPs exhibit species difference in expressed tissues and functional properties between human and animals, human studies are essential to clarify the intestinal absorption mechanisms of drugs via OATPs. Recent pharmacogenomic studies demonstrated that OATP2B1 is involved in the drug absorption in human. In addition, information of drug-juice interaction in the intestine also uncovered the contribution of OATP1A2 and OATP2B1 in drug absorption. Since OATP1A2 and OATP2B1 exhibit broader substrate selectivity compared with PEPT1, their potential to be applied for oral delivery should be high. In this review, current understanding of characteristics and contribution as the absorptive transporters of OATPs in small intestine in human is described. Now, it is getting clearer that OATPs have significant roles in intestinal absorption of drugs, therefore, there are higher possibility to utilize OATPs as the tools for oral delivery. © 2011 Elsevier B.V. All rights reserved
Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21)
The carnitine/organic cation transporter (OCTN) family consists of three transporter isoforms, i.e. OCTN1 (SLC22A4) and OCTN2 (SLC22A5) in humans and animals and Octn3 (Slc22a21) in mice. These transporters are physiologically essential to maintain appropriate systemic and tissue concentrations of carnitine by regulating its membrane transport during intestinal absorption, tissue distribution and renal reabsorption. Among them, OCTN2 is a sodium-dependent, high-affinity transporter of carnitine, and a functional defect of OCTN2 due to genetic mutation causes primary systemic carnitine deficiency (SCD). Since carnitine is essential for beta-oxidation of long-chain fatty acids to produce ATP, OCTN2 gene mutation causes a range of symptoms, including cardiomyopathy, skeletal muscle weakness, fatty liver and male infertility. These functional consequences of Octn2 gene mutation can be seen clearly in an animal model, jvs mouse, which exhibits the SCD phenotype. In addition, although the mechanism is not clear, single nucleotide polymorphisms of OCTN1 and OCTN2 genes are associated with increased incidences of rheumatoid arthritis, Crohn\u27s disease and asthma. OCTN1 and OCTN2 accept cationic drugs as substrates and contribute to intestinal and pulmonary absorption, tissue distribution (including to tumour cells), and renal excretion of these drugs. Modulation of the transport activity of OCTN2 by externally administered drugs may cause drug-induced secondary carnitine deficiency. Octn3 transports carnitine specifically, particularly in male reproductive tissues. Thus, the OCTNs are physiologically, pathologically and pharmacologically important. Detailed characterization of these transporters will greatly improve our understanding of the pathology associated with common diseases caused by functional deficiency of OCTNs. © 2012 John Wiley & Sons, Ltd
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å¶åŸ¡æ³ã®å¯èœæ§ã匷ã瀺ããã®ã§ãããVarious transporters that mediate membrane transport of drugs as well as physiological compounds were clarified by molecular cloning of the genes and their functional analysis by gene expression systems. The obtained results are as follows :1. Novel transporter family OCTNs were molecularly cloned and their transport functions were analyzed by transfection of the gene to HEK293 cells. Human and mouse OCTN2 transported physiologically important carnitine in a sodium dependent manner. JVS mice that show systemic carnitine deficiency(SCD) syndrome had a mutation in OCTN2 gene with loss of carnitine transport function. Furthermore, various mutations in OCTN2 gene were identified in patients who show the SCD syndrome. From these results, it was clarified that OCTN2 is a physiologically important camitine transporter and its mutation leads to the SCD. Interestingly, OCTN2 and its isoform OCTN1 transported organic cations in a sodium independent manner. Accordingly, OCTNs are unique transporters which have are multifunctionality by transporting carnitine and organic cations in the distinct mechanisms.2. Molecular characterization of the transporter for monocarboxylic acids at the blood-brain barrier (BBB) was performed. Monocarboxylic acid transporter MCT-1 gene was expressed at the BBB and was found to play important role in the transport of organic weak acids by the in vitro cultured cells and in vivo studies.3. Multiple efflux mechanisms for new quinolone antibacterial agent were found to be expressed at the BBB. They are P-glycoprotein and unknown transporters sensitive to anionic compounds. These multiple efflux transporters seem to restrict the brain distribution of quinolones and other drugs, resulting in a low distribution into the central nervous system.These lines of studies provide new insight of the siginificance of membrane transporters and new strategy to control disposition of drugs by focusing on the transporters function present in various tissues.ç 究課é¡/é åçªå·:10470510, ç 究æé(幎床):1997-199
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å ±ãäžãããã®ãšãªã£ããIn the present study, we studied membrane transporters equippecd, in the brain capillary endothelial cells that are functional as the blood-brain barrier. Through this study, we found three new transporters that are expressed at the blood-brain barrier.One of those transporters are monocarboxylic acid transporter MGT1, which tworks for uptake and/or efflux organic weak acids such as lactic acid, pyruvic acid and benzoic acid. The second transporter is neutral amino acid transporters LAT1 and LAT2. These two amino acid transporters work for the uptake of amino acids that are relatively hydrdphpbic and large molecules, including leucine, tyrosine and phenylalanine. These are also important for the brain livery of L-DOPA that is effective for perkinsonism. The third transporter is OCTN2that is callsified as the carnitine/organic cation transporter. OCTN2 is a Na^+-dependent carnitine transporter and works for the brain uptake of acetyl-L-carhitirie that is expected to be useful for Aitzhe imer\u27s disease. On the other hand, brain efflux transporters that protect brain from the toxic xenobiotics. As the model drugs, H1-antagonist, ebastine and carebasitine and fluoroquinolone, grepafloxacine, was used in the present study. Generally, fluoroquinolonesand H1 antagonists exhibit adverse effects such as epilepsy and sedative effects, while the drugs studied in the present study do not show such adverse effects. We expected that these drugs might not have enough permeability across the blood-brain barrier, resulting in the insufficient delivery to the brain to cause unfavorable adverse effects. Varipus Kinds of studies on the BBB transport of these drugs demonstrated that there are at least two types of brain efflux transporters, including p-glycoproteih and anion exchange transporter, of which molecular identification remains to be succeeded.All of these studies were performed by using various BBB-transport techniques. Especially, newly developed cell line RBEC1 that were derived from rat brain capillary endothelial cells was useful for the success of the present study. Furthermore, we challenged of the coculture of the endothelial cells and astrocytes in order to mimic the in vivo BBB. Although we partly succeeded to prepare the in vitro BBB model, further improvement will be essential for the efficient and complete model for the evaluation of blood-brain barrier transport.ç 究課é¡/é åçªå·:12557229, ç 究æé(幎床):2000-2001åºå
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