Genetic Variation in the Renal Sodium Transporters NKCC2, NCC, and ENaC in Relation to the Effects of Loop Diuretic Drugs

There is little data on genetic predictors of loop diuretic efficacy in humans. Therefore, we investigated the diuretic effects of single oral doses of bumetanide, frusemide, and torsemide in a crossover study in 97 healthy Caucasians in relation to genetic variation in the renal sodium transporters...

Full description

Saved in:
Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2007-09, Vol.82 (3), p.300-309
Main Authors: Vormfelde, S V, Sehrt, D, Toliat, M R, Schirmer, M, Meineke, I, Tzvetkov, M, Nürnberg, P, Brockmöller, J
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
Bumetanide - pharmacokinetics
Bumetanide - pharmacology
Cross-Over Studies
Diuretics - pharmacokinetics
Diuretics - pharmacology
Epithelial Sodium Channels - genetics
Furosemide - pharmacokinetics
Furosemide - pharmacology
Genotype
Haplotypes
Humans
Kidney - metabolism
Male
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Phenotype
Polymorphism, Genetic - genetics
Potassium - metabolism
Receptors, Drug - genetics
Sodium-Potassium-Chloride Symporters - genetics
Solute Carrier Family 12, Member 1
Solute Carrier Family 12, Member 3
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
Symporters - genetics
Thiazides - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:There is little data on genetic predictors of loop diuretic efficacy in humans. Therefore, we investigated the diuretic effects of single oral doses of bumetanide, frusemide, and torsemide in a crossover study in 97 healthy Caucasians in relation to genetic variation in the renal sodium transporters NKCC2 (coded by SLC12A1), NCC (SLC12A3), and ENaC (three subunits coded by SCNN1A, SCNN1B, and SCNN1G). The NCC alanine 264 allele (Gly264Ala) and the most frequent SCNN1B haplotype were associated with stronger diuresis, indicating lower reabsorbing function of these alleles. The variant alleles of the tightly coupled polymorphisms rs5723 (Leu649Leu) and rs5729 in SCNN1G were associated with weaker diuresis, indicating higher activity. Extended haplotype homozygosity implied evolutionary selection of the NCC alanine 264 allele. In conclusion, acute diuretic effects of loop diuretics were affected by genetic variation in sodium transporters that, in the nephron, are located distally from NKCC2. Clinical Pharmacology & Therapeutics (2007) 82, 300–309; doi:10.1038/sj.clpt.6100131; published online 25 April 2007
ISSN:0009-9236
1532-6535
DOI:10.1038/sj.clpt.6100131