Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive rats

Abstract

Abstract: AIM: Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive rats at non-steady-state and steady-state. METHODS: The renal hypertensive rats were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Systolic and diastolic blood pressure and plasma concentrations were measured after single- and multi- dosing and PK/PD parameters were analyzed. RESULTS: Irbesartan showed a two-compartment model pharmacokinetic profile. The concentration-time course of irbesartan was not changed by HCTZ, but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis phenomenon was found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis phenomenon disappeared at steady state with more rapid realization of maximum concentration and effects. The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model. CONCLUSION: The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive rats and some differences of PK/PD properties between irbesartan and irbesartan/HCTZ combinations at non-steady state and steady state. These comparisons are likely to be clinically significant.

Key words: Irbesartan, Hydrochlorothiazide, Pharmacokinetics, Pharmacodynamics, Drug interaction

CLC Number:

R969

HUANG Xiao-hui, HUANG Ji-han, CHEN Yun, QIU Fu-rong, LI Jun, SUN Rui-yuan. Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(3): 294-301.

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