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

Abstract

AimsTo 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. MethodsWe 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 . ResultsIn stably transfected HEK293 cells torsemide (100 µ M ) 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. ConclusionsGenetic variation in the gene encoding the luminally expressed OAT4 rather than in the basolaterally expressed OATs may affect the renal clearance of torsemide.

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

“…However, there is evidence that genetic polymorphisms of these transporters are not associated with the pharmacokinetics of several drugs, including tenofovir, adefovir, prava- statin, and torsemide (9,(23)(24)(25). Therefore, the transportation of drugs across the apical membrane (from cell to tubular lumen) by multidrug-resistant proteins may be a rate-limiting step for drug secretion (23,25). Thus, it is likely that the polymorphisms of organic anion transporters may not be associated with tenofovir's pharmacokinetics.…”

Gender Is an Important Determinant of the Disposition of the Loop Diuretic Torasemide

“…Interindividual differences in renal clearance of torasemide have been partially explained by genetic variation in the luminally expressed organic anion transporter OAT4 (SLC22A11). 14,15 The objective of the present study was to quantify the impact of gender on torasemide pharmacokinetics during steady state in the hospital setting. Studies on determinants of torasemide pharmacokinetics in patients during steady-state treatment are largely missing.…”

Current Updates in the Genetic Polymorphisms of Human Organic Anion Transporters (OATs)

“…Further kinetic studies revealed that both K m and V max of R50H and R293W variants, were not considerably distinct from the reference in the influx of PAH and OTA [2]. Likewise, Vormfelde et al [56] indicated that four genetic variations with the highest allele frequency of 0.29 had no effect on the torsemide renal clearance. Up to now, the protein expressions of OAT1 genetic variants has not yet been investigated.…”

“…All the other variants assessed in the same study did not show a considerable difference in the uptake of either substrate [1,59]. More recently, Vormfelde et al [56] molecularly investigated two 5' UTR and one non-synonymous SNPs of OAT3, and none of these SNPs was shown to affect the renal clearance of the loop diuretic, torsemide.…”

“…The studies of us and others have also reported the functional analysis of several OAT4 genetic variants. In the study of 95 individuals, Vormfelde et al [56] observed 10 polymorphisms in the 5' or the 3' UTRs, or the introns. Human subject carrying the SNP (rs11231809), showed the most pronounced decrease in torsemide clearance.…”