title: Pharmacokinetics of temocapril and temocaprilat after 14 once daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment.
abstract: OBJECTIVE
  The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat.
  
  
  METHODS
  Non-compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal (creatinine clearance determined via 24 h urine sampling, CL[CR], > or = 60 ml min-1) and impaired renal function (CL[CR] 40-59, 20-39, < 20 ml min-1) after 14 once daily oral doses of 10 mg temocapril hydrochloride.
  
  
  RESULTS
  For temocapril, there were no statistically significant differences in median tmax or mean Cmax, AUC(SS), t1/2,Z, CL/F between the four groups. Renal clearance, CL(R), for temocapril showed a linear decreasing trend with decreasing CL(CR) [mean (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min-1]. Steady-state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean Cmax or median tma were detected. With decreasing mean CL(CR), mean AUC(SS) for temocaprilat increased statistically significantly although only 2.4-fold [mean (s.d.): 2115 (565) to 4989 (2338) ng ml-1 h] and t1/2,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CL(R) for temocaprilat showed a linear decreasing trend with decreasing CL(CR) [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min-1].
  
  
  CONCLUSIONS
  These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug.
authors.affiliation: Sankyo Europe GmbH, Duesseldorf, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Püchler
authors.forename: K M
authors.initials: KM
authors.lastname: Eckl
authors.forename: L
authors.initials: L
authors.lastname: Fritsche
authors.forename: K
authors.initials: K
authors.lastname: Renneisen
authors.forename: H H
authors.initials: HH
authors.lastname: Neumayer
authors.forename: B
authors.initials: B
authors.lastname: Sierakowski
authors.forename: A T
authors.initials: AT
authors.lastname: Lavrijssen
authors.forename: T
authors.initials: T
authors.lastname: Thomsen
authors.forename: I
authors.initials: I
authors.lastname: Roots
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013841:Thiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D013841:Thiazepines; C069156:temocaprilat; C055603:temocapril hydrochloride; D003404:Creatinine