title: The pharmacokinetics of losartan in renal insufficiency.
abstract: OBJECTIVE
  To determine the effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of losartan (MK-954) and its metabolite E3174.
  
  
  METHODS
  A two-center, unblinded trial was performed in 18 patients (age range 31-63 years) with various degrees of renal function grouped according to the renal clearance of creatinine: group I, creatinine clearance > or = 75 ml/min; group II, creatinine clearance 30-74 ml/min; group III, creatinine clearance 10-29 ml/min (n = 6 in all groups). Losartan (100 mg/day) was administered under supervised conditions for seven consecutive days. Plasma samples were taken for up to 60 h and 24-h urine collections were made following the final dose of losartan (on day 7) to determine losartan and E3174 concentrations, with simultaneous measurements of blood pressure and the pulse rate.
  
  
  RESULTS
  The pharmacokinetic parameters for losartan and E3174 changed inconsequentially across the range of renal insufficiency. For losartan, renal clearance decreased from 50 +/- 19 ml/min in group I to 2.3 +/- 0.9 ml/min in group III (P < 0.05). For E3174, although the renal clearance decreased from 16 +/- 4.1 ml/min in group I to 1.3 +/- 0.8 ml/min in group III (P < 0.05), the area under the plasma concentration curve did not change.
  
  
  CONCLUSIONS
  The steady-state areas under the curve of losartan and E3174 are not significantly changed with renal impairment. The renal clearance of losartan decreases with renal impairment but since only a small percentage of the dose is ordinarily eliminated by the kidney, the demonstrated reduction in clearance is clinically irrelevant. The renal clearance of E3174 also decreases with renal impairment, but the steady-state area under the curve does not increase with increasing degrees of renal insufficiency. These pharmacokinetic alterations do not warrant dose adjustment in the face of renal insufficiency.
authors.affiliation: Division of Clinical Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0160, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Sica
authors.forename: M W
authors.initials: MW
authors.lastname: Lo
authors.forename: W C
authors.initials: WC
authors.lastname: Shaw
authors.forename: W F
authors.initials: WF
authors.lastname: Keane
authors.forename: T W
authors.initials: TW
authors.lastname: Gehr
authors.forename: C E
authors.initials: CE
authors.lastname: Halstenson
authors.forename: K
authors.initials: K
authors.lastname: Lipschutz
authors.forename: C I
authors.initials: CI
authors.lastname: Furtek
authors.forename: M A
authors.initials: MA
authors.lastname: Ritter
authors.forename: S
authors.initials: S
authors.lastname: Shahinfar
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003404:Creatinine / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D019808:Losartan / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000378:metabolism*; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
chemical_list: D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; D003404:Creatinine; C066026:losartan carboxylic acid; D019808:Losartan