title: Determinants of steady-state torasemide pharmacokinetics: impact of pharmacogenetic factors, gender and angiotensin II receptor blockers.
abstract: BACKGROUND
  Torasemide is frequently used for the treatment of hypertension and heart failure. However, the determinants of torasemide pharmacokinetics in patients during steady-state conditions are largely unknown. We therefore explored the impact of genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and organic anion transporting polypeptide (OATP) 1B1 (SLCO1B1), gender, and the effects of losartan and irbesartan comedication on the interindividual variability of steady-state pharmacokinetics of torasemide.
  
  
  METHODS
  Twenty-four patients receiving stable medication with torasemide 10 mg once daily and with an indication for additional angiotensin II receptor blocker (ARB) treatment to control hypertension or to treat heart failure were selected. Blood samples were taken before torasemide administration and 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. After this first study period, patients received either irbesartan 150 mg (five female and seven male patients aged 69+/-8 years) or losartan 100 mg (two female and ten male patients aged 61+/-8 years) once daily. After 3 days of ARB medication, eight blood samples were again collected at the timepoints indicated above. The patients' long-term medications, which did not include known CYP2C9 inhibitors, were maintained at a constant dose during the study. All patients were genotyped for CYP2C9 (*1/*1 [n=15]; *1/*2 [n = 4]; *1/*3 [n=5]) as well as for SLCO1B1 (c.521TT [n=13]; c.521TC [n=11]).
  
  
  RESULTS
  Factorial ANOVA revealed an independent impact of the CYP2C9 genotype (dose-normalized area under the plasma concentration-time curve during the 24-hour dosing interval at steady state [AUC(24,ss)/D]: *1/*1 375.5+/-151.4 microg x h/L/mg vs *1/*3 548.5+/-271.6 microg x h/L/mg, p=0.001), the SLCO1B1 genotype (AUC(24,ss)/D: TT 352.3+/-114 microg x h/L/mg vs TC 487.6+/-218.4 microg x h/L/mg, p<0.05) and gender (AUC(24,ss)/D: males 359.5+/-72.2 microg x h/L/mg vs females 547.3+/-284 microg x h/L/mg, p<0.01) on disposition of torasemide. Coadministration of irbesartan caused a 13% increase in the AUC(24,ss)/D of torasemide (p=0.002), whereas losartan had no effect.
  
  
  CONCLUSIONS
  This study shows that the CYP2C9*3 and SLCO1B1 c.521TC genotype and female gender are significant and independent predictors of the pharmacokinetics of torasemide. Coadministration of irbesartan yields moderate but significant increases in the torasemide plasma concentration and elimination half-life.
authors.affiliation: Department of Cardiology, Helios-Hospital Schwerin, Schwerin, Germany. dierk.werner@arcor.de
authors.forename: Dierk
authors.initials: D
authors.lastname: Werner
authors.forename: Ulrike
authors.initials: U
authors.lastname: Werner
authors.forename: Annett
authors.initials: A
authors.lastname: Meybaum
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
authors.forename: Sumaira
authors.initials: S
authors.lastname: Umbreen
authors.forename: Anton
authors.initials: A
authors.lastname: Grosch
authors.forename: Heiko G
authors.initials: HG
authors.lastname: Lestin
authors.forename: Bernhard
authors.initials: B
authors.lastname: Graf
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D012727:Sex Characteristics; D013449:Sulfonamides / Q000493:pharmacokinetics*; D000077786:Torsemide
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000077786:Torsemide