Torsemide renal clearance and genetic variation in luminal and basolateral organic anion transporters

• Published in: British journal of clinical pharmacology Vol. 62; no. 3; pp. 323 - 335
• Main Authors: Vormfelde, Stefan V., Schirmer, Markus, Hagos, Yohannes, Toliat, Mohammad R., Engelhardt, Sabine, Meineke, Ingolf, Burckhardt, Gerhard, Nürnberg, Peter, Brockmöller, Jürgen
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2006; Blackwell Science
• Subjects: Adult; Biological and medical sciences; Diuretics - pharmacokinetics; Genetic Linkage - genetics; Genetic Variation; haplotype; Haplotypes - genetics; Humans; Kidney - metabolism; Male; Medical sciences; Middle Aged; organic anion transporter; Organic Anion Transporters - genetics; Pharmacogenetics; Pharmacology. Drug treatments; Polymerase Chain Reaction; polymorphism; Polymorphism, Genetic - genetics; renal clearance; SLC22A11; Sulfonamides - pharmacokinetics; torsemide; Genetic variability; renal clearance; organic anion transporter; Genotype; Clearance; torsemide; Kidney; Organic anion; Urinary system; Pharmacokinetics; Haplotype; Carrier protein; Polymorphism; SLC22A11
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2006.02655.x

Aims 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 µm) 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.