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Physiological and pharmacological ro...

Urban, Thomas J.

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Physiological and pharmacological roles of novel organic cation transporters.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Physiological and pharmacological roles of novel organic cation transporters./
Author:	Urban, Thomas J.
Description:	237 p.
Notes:	Adviser: Kathleen M Giacomini.
Contained By:	Dissertation Abstracts International68-04B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3261226

Physiological and pharmacological roles of novel organic cation transporters.
Urban, Thomas J.

Physiological and pharmacological roles of novel organic cation transporters. - 237 p.

Adviser: Kathleen M Giacomini.

Thesis (Ph.D.)--University of California, San Francisco, 2007.

The novel organic cation transporters (OCTNs) are bifunctional and bidirectional tranporters that are highly expressed at the apical membrane in renal tubular epithelia, and are thought to contribute to both the renal salvage of nutrients and to the active tubular secretion of xenobiotics. We used a genotype-to-phenotype approach to study the importance of OCTN1 (encoded by SLC22A4) and OCTN2 (encoded by SLC22A5) in the disposition of drugs and endobiotics. Resequencing of the coding region of these genes in a large ethnically-diverse sample of human DNA revealed six amino acid-altering nucleotide substitutions in SLC22A4 and eight in SLC22A5. When expressed heterologously, several rare variants of OCTN1 (D165G, R282X) were found to result in complete loss of transport function. Rare OCTN2 variants showed functional differences from the reference protein, including reduced function (V481F) and substrate selectivity differences (Y449D). Functionally significant single-nucleotide polymorphisms (SNPs) in OCTN1 (L503F) and OCTN2 (-207G>C and F17L) were also discovered. These common SNPs were tested for functional significance in vivo by recruiting subjects based on genotype at these positions, and testing for quantitative differences between genotype groups in the pharmacokinetics of gabapentin (an OCTN1 substrate) and carnitine (a preferred substrate of OCTN2). OCTN1 genotype was found to be a significant predictor of gabapentin renal clearance, with OCTN1 reference homozygotes showing net active secretion of gabapentin, but L503F homozygotes showing almost no active secretion of this drug. This finding adds the OCTN1-L503F polymorphism to a small list of SNPs known to influence drug disposition. OCTN genotype did not affect carnitine disposition or lipid metabolism. A meta-analysis of protein-altering variants of membrane transporters revealed that, as exemplified by the OCTNs, rare variants are more likely to affect global biochemical function; however, variants with substrate-specific effects (such as the OCTN1-L503F variant) may be relatively common. The results of this research support the hypothesis that OCTN transporters are important determinants of active drug secretion in the kidney, and that prediction of renal clearance of drugs may be improved by renal transporter genotype information. This research may help to inform future pharmacogenetic studies of the OCTN transporters, and renal drug transporters generally.Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Physiological and pharmacological roles of novel organic cation transporters.
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035 $a (UMI)AAI3261226
035 $a AAI3261226
040 $a UMI $c UMI
100 1 $a Urban, Thomas J. $3 1267698
245 1 0 $a Physiological and pharmacological roles of novel organic cation transporters.
300 $a 237 p.
500 $a Adviser: Kathleen M Giacomini.
500 $a Source: Dissertation Abstracts International, Volume: 68-04, Section: B, page: 2280.
502 $a Thesis (Ph.D.)--University of California, San Francisco, 2007.
520 $a The novel organic cation transporters (OCTNs) are bifunctional and bidirectional tranporters that are highly expressed at the apical membrane in renal tubular epithelia, and are thought to contribute to both the renal salvage of nutrients and to the active tubular secretion of xenobiotics. We used a genotype-to-phenotype approach to study the importance of OCTN1 (encoded by SLC22A4) and OCTN2 (encoded by SLC22A5) in the disposition of drugs and endobiotics. Resequencing of the coding region of these genes in a large ethnically-diverse sample of human DNA revealed six amino acid-altering nucleotide substitutions in SLC22A4 and eight in SLC22A5. When expressed heterologously, several rare variants of OCTN1 (D165G, R282X) were found to result in complete loss of transport function. Rare OCTN2 variants showed functional differences from the reference protein, including reduced function (V481F) and substrate selectivity differences (Y449D). Functionally significant single-nucleotide polymorphisms (SNPs) in OCTN1 (L503F) and OCTN2 (-207G>C and F17L) were also discovered. These common SNPs were tested for functional significance in vivo by recruiting subjects based on genotype at these positions, and testing for quantitative differences between genotype groups in the pharmacokinetics of gabapentin (an OCTN1 substrate) and carnitine (a preferred substrate of OCTN2). OCTN1 genotype was found to be a significant predictor of gabapentin renal clearance, with OCTN1 reference homozygotes showing net active secretion of gabapentin, but L503F homozygotes showing almost no active secretion of this drug. This finding adds the OCTN1-L503F polymorphism to a small list of SNPs known to influence drug disposition. OCTN genotype did not affect carnitine disposition or lipid metabolism. A meta-analysis of protein-altering variants of membrane transporters revealed that, as exemplified by the OCTNs, rare variants are more likely to affect global biochemical function; however, variants with substrate-specific effects (such as the OCTN1-L503F variant) may be relatively common. The results of this research support the hypothesis that OCTN transporters are important determinants of active drug secretion in the kidney, and that prediction of renal clearance of drugs may be improved by renal transporter genotype information. This research may help to inform future pharmacogenetic studies of the OCTN transporters, and renal drug transporters generally.
590 $a School code: 0034.
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
710 2 $a University of California, San Francisco. $b Pharmaceutical Sciences and Pharmacogenomics. $3 1023490
773 0 $t Dissertation Abstracts International $g 68-04B.
790 $a 0034
790 1 0 $a Giacomini, Kathleen M, $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3261226