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 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.
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 microm) inhibited the uptake by humanOAT1, 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.
Authors: Kourosh R Ahmadi; Mike E Weale; Zhengyu Y Xue; Nicole Soranzo; David P Yarnall; James D Briley; Yuka Maruyama; Mikiro Kobayashi; Nicholas W Wood; Nigel K Spurr; Daniel K Burns; Allen D Roses; Ann M Saunders; David B Goldstein Journal: Nat Genet Date: 2004-12-19 Impact factor: 38.330
Authors: Stefan Viktor Vormfelde; Sabine Engelhardt; Alexandra Zirk; Ingolf Meineke; Franziska Tuchen; Julia Kirchheiner; Jürgen Brockmöller Journal: Clin Pharmacol Ther Date: 2004-12 Impact factor: 6.875
Authors: Tomoe Fujita; Chaline Brown; Elaine J Carlson; Travis Taylor; Melanie de la Cruz; Susan J Johns; Doug Stryke; Michiko Kawamoto; Kazumi Fujita; Richard Castro; Chung-Wen Chen; Emil T Lin; Claire M Brett; Esteban Gonzalez Burchard; Thomas E Ferrin; Conrad C Huang; Maya K Leabman; Kathleen M Giacomini Journal: Pharmacogenet Genomics Date: 2005-04 Impact factor: 2.089
Authors: Kelly Bleasby; Laura A Hall; Jennifer L Perry; Harvey W Mohrenweiser; John B Pritchard Journal: J Pharmacol Exp Ther Date: 2005-05-24 Impact factor: 4.030
Authors: Eleftheria Zeggini; Anne Barton; Stephen Eyre; Daniel Ward; William Ollier; Jane Worthington; Sally John Journal: BMC Genet Date: 2005-04-25 Impact factor: 2.797
Authors: Jan Schiefer; Holger Amthauer; Philipp Genseke; Peter R Mertens; Christos Chatzikyrkou Journal: Int Urol Nephrol Date: 2017-07-11 Impact factor: 2.370
Authors: Dierk Werner; Ulrike Werner; Annett Meybaum; Boris Schmidt; Sumaira Umbreen; Anton Grosch; Heiko G Lestin; Bernhard Graf; Oliver Zolk; Martin F Fromm Journal: Clin Pharmacokinet Date: 2008 Impact factor: 6.447
Authors: Sook Wah Yee; Anh Nguyet Nguyen; Chaline Brown; Radojka M Savic; Youcai Zhang; Richard A Castro; Cheryl D Cropp; Ji Ha Choi; Diment Singh; Harunobu Tahara; Sophie L Stocker; Yong Huang; Claire M Brett; Kathleen M Giacomini Journal: J Pharm Sci Date: 2013-05-06 Impact factor: 3.534