title: Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats.
abstract: OBJECTIVE
  To investigate the pharmacokinetic (PK) and the pharmacodynamic (PD) properties of telmisartan in spontaneously hypertensive (SH) rats using an indirect response and effect-compartment link models, and compare two PK-PD models fitting quality.
  
  
  METHODS
  The SH rats received a single oral dose of 2, 4, and 8 mg/kg of telmisartan. The plasma concentrations of telmisartan were determined by the liquid chromatography-mass spectrum method. The mean arterial blood pressure was measured to characterize the pharmacodynamics of telmisartan by tail-cuff manometry. The relationship for the telmisartan concentration-hypotensive effect in the SH rats was characterized using an indirect response model.
  
  
  RESULTS
  The PK parameters showed dose proportionality, with a long terminal half-life of 16 h, a clearance of 0.15 Lxkg( -1) xh( -1), and a volume of distribution of 5.36 Lxkg( -1) in the study. For the indirect response PD model, the estimated K(in) were 36.6, 34.1, and 32.8 %.h( -1), K(out) were 36.7, 34.6, and 31.9 h( -1); the IC(50) values were 86.2, 95.8, and 91.1 ngxmL( -1); and the area under the effect curve (AUEC) were 762.8, 1490.5, and 2086.2 mmHg.h at three doses, respectively. For the effect-compartment model, the K(eo) were 29.4, 33.8, and 28.7 h( -1); the IC(50) values were 78.2, 85.7, and 80.9 ngxmL(-1), and the AUEC were 781.5, 1602.8, and 2215.7 mmHg.h at three doses, respectively.
  
  
  CONCLUSIONS
  According to Akaike's information criterion values, the proposed indirect response model provided a more appropriate and good-fitting PK/PD characterization of telmisartan than the effect-compartment link model in SH rats.
authors: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Kun
authors: K
authors: Hao
authors: Yuan-Cheng
authors: YC
authors: Chen
authors: Yan-Guang
authors: YG
authors: Cao
authors: Dan
authors: D
authors: Yu
authors: Xiao-Quan
authors: XQ
authors: Liu
authors: Guang-Ji
authors: GJ
authors: Wang
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D001565:Benzoates / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D008954:Models, Biological; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D000077333:Telmisartan