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 L·kg−1·h−1, and a volume of distribution of 5.36 L·kg−1 in the study. For the indirect response PD model, the estimated Kin were 36.6, 34.1, and 32.8 %·h−1, Kout were 36.7, 34.6, and 31.9 h−1; the IC50 values were 86.2, 95.8, and 91.1 ng·mL−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 Keo were 29.4, 33.8, and 28.7 h−1; the IC50 values were 78.2, 85.7, and 80.9 ng·mL−1, and the AUEC were 781.5, 1602.8, and 2215.7 mmHg-hat 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.
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Project supported by the National High Technology “863” Project (No 2003AA2Z-347A) and Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics (No BM2001201).
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Hao, K., Chen, Yc., Cao, Yg. et al. Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats. Acta Pharmacol Sin 28, 738–743 (2007). https://doi.org/10.1111/j.1745-7254.2007.00556.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00556.x
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