Significant progress has been made in understanding the subcellular mechanisms involved in the metabolism of drugs. In contrast, little is known about the mechanisms involved in the other major pathway of drug elimination, renal excretion. The organic cation transport system of the renal proximal tubule is responsible for the active secretion from the body of many important basic drugs including procainamide, cimetidine, morphine and certain beta adrenoreceptor blocking agents. The overall goals of the proposed studies are to elucidate the cellular mechanisms of the organic cation transport system and to determine the biologic relevance of these findings to the mechanisms of transport of basic drugs. The mechanisms of the system will be investigated using a model organic cation, N1-methylnicotinamide (NMN).
The specific aims of these studies are to: (1) characterize the transport of NMN in the luminal and antiluminal membrane of the renal proximal tubule; (2) test ion gradients as possible driving forces for organic cation transport in the two membranes; (3) elucidate the electrogenecity of organic cation transport in the antiluminal and luminal membrane; (4) determine whether the transport systems in both membranes function as specific pores or mobile carriers; (5) delineate the specific functional groups that are essential for organic cation transport in the two membranes; In addition, the mechanisms of transport of model drug, procainamide, will be studied. Luminal and antiluminal membrane vesicles will be prepared from rabbit renal cortex. Isotopic studies of 3H-NMN and 3H-procainamide will be studied. Michaelis-Menten parameters of each of the compounds in both membranes will be determined. The effect of various ion gradients on uptake of 3H-NMN will be determined. In addition, the studies will make use of pH-gradient fluorescent probes and potential sensitive probes. Modifying reagents will be used to determine the relevant functional groups for transport in both membranes. Clinically, many important drugs are eliminated from the body by the organic cation transport system. Knowledge of the mechanisms involved in the system will enhance the rational use of these compounds. The studies with procainamide will elucidate the relevance of these mechanisms to a clinically important drug. These studies will ultimately lead to a more sophisticated knowledge of the renal elimination of drugs.
|Chen, Ligong; Shu, Yan; Liang, Xiaomin et al. (2014) OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A 111:9983-8|
|Yee, Sook Wah; Chen, Ligong; Giacomini, Kathleen M (2012) The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet 44:359-60|
|Minematsu, Tsuyoshi; Giacomini, Kathleen M (2011) Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther 10:531-9|
|Li, Shuanglian; Chen, Ying; Zhang, Shuzhong et al. (2011) Role of organic cation transporter 1, OCT1 in the pharmacokinetics and toxicity of cis-diammine(pyridine)chloroplatinum(II) and oxaliplatin in mice. Pharm Res 28:610-25|
|Choi, J H; Yee, S W; Ramirez, A H et al. (2011) A common 5'-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther 90:674-84|
|More, Swati S; Itsara, Melissa; Yang, Xiaodong et al. (2011) Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems. Clin Cancer Res 17:2339-49|
|Kido, Yasuto; Matsson, Pär; Giacomini, Kathleen M (2011) Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem 54:4548-58|
|More, Swati S; Akil, Omar; Ianculescu, Alexandra G et al. (2010) Role of the copper transporter, CTR1, in platinum-induced ototoxicity. J Neurosci 30:9500-9|
|Ianculescu, Alexandra G; Friesema, Edith C H; Visser, Theo J et al. (2010) Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine. Mol Biosyst 6:1403-10|
|Chen, Ligong; Takizawa, Miho; Chen, Eugene et al. (2010) Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function. J Pharmacol Exp Ther 335:42-50|
Showing the most recent 10 out of 70 publications