Torsemide renal clearance and genetic variation in luminal and basolateral organic anion transporters.
OBJECTIVE
To investigate the association between torsemide renal clearance and genetic variation in the basolaterally expressed renal organic anion transporters OAT1 and OAT3 and in the luminally situated OAT4.


METHODS
We analysed 22 polymorphisms in the OAT coding genes SLC22A6, SLC22A8 and SLC22A11 and their haplotypes and measured torsemide renal clearance in 95 healthy men. In addition, the effect of torsemide on the OAT-mediated transport was studied in vitro.


RESULTS
In stably transfected HEK293 cells torsemide (100 microm) inhibited the uptake by human OAT1, OAT3 and OAT4 by 63.1, 58.1 and 68.0%, respectively. Torsemide renal clearance ranged from 6.5 to 43.1 ml min(-1) with a log-normal distribution and a geometric mean of 15.6 ml min(-1) (15.0-16.1 +/- SEM). No clear outlier group was observed. AA carriers of the polymorphism rs11231809 in SLC22A11 had a torsemide renal clearance of 13.3 ml min(-1) (12.7-13.9) compared with 15.1 ml min(-1) (14.5-15.8) in AT and 18.0 ml min(-1) (16.7-19.5) in TT carriers (P = 0.002). The two most frequent haplotypes at SLC22A11 showed an association with torsemide renal clearance. Homozygous carriage of these two haplotypes resulted in renal clearances of 21.2 ml min(-1) (19.0-23.7) and 11.8 ml min(-1) (10.5-13.5), respectively. No association between reanl clearance and genetic variation in SLC22A6 or SLC22A8 was observed.


CONCLUSIONS
Genetic variation in the gene encoding the luminally expressed OAT4 rather than in the basolaterally expressed OATs may affect the renal clearance of torsemide.
Vormfelde
Stefan V
SV
Centre of Physiology and Pathophysiology, Georg-August University Göttingen, Göttingen, Germany. svormfe@gwdg.de
Schirmer
Markus
M
Hagos
Yohannes
Y
Toliat
Mohammad R
MR
Engelhardt
Sabine
S
Meineke
Ingolf
I
Burckhardt
Gerhard
G
Nürnberg
Peter
P
Brockmöller
Jürgen
J
D000328:Adult; D004232:Diuretics / Q000493:pharmacokinetics*; D008040:Genetic Linkage / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*; D000077786:Torsemide
D004232:Diuretics; D027361:Organic Anion Transporters; D013449:Sulfonamides; D000077786:Torsemide