Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats

Acta Pharmacol Sin. 2007 May;28(5):738-43. doi: 10.1111/j.1745-7254.2007.00556.x.

Abstract

Aim: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacokinetics*
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Antihypertensive Agents / pharmacokinetics*
  • Antihypertensive Agents / pharmacology
  • Benzimidazoles / pharmacokinetics*
  • Benzimidazoles / pharmacology
  • Benzoates / pharmacokinetics*
  • Benzoates / pharmacology
  • Blood Pressure / drug effects
  • Dose-Response Relationship, Drug
  • Male
  • Models, Biological*
  • Random Allocation
  • Rats
  • Rats, Inbred SHR*
  • Telmisartan

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Antihypertensive Agents
  • Benzimidazoles
  • Benzoates
  • Telmisartan