Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive dogs.
Combined irbesartan/hydrochlorothiazide (HCTZ) formulations are often used clinically. Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs at non-steady-state and steady-state. The renal hypertensive dogs were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Blood pressure and plasma concentrations were measured and pharmacokinetic-pharmacodynamic parameters were analyzed. 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. HCTZ had no blood pressure lowering effect at non-steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis loops were found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis loops 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. The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs and some differences of pharmacokinetic-pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady state.
Huang
Xiao-Hui
XH
College of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.
Qiu
Fu-Rong
FR
Xie
Hai-Tang
HT
Li
Jun
J
D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006852:Hydrochlorothiazide / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006977:Hypertension, Renal / Q000188:drug therapy*; D000077405:Irbesartan; D008954:Models, Biological; D013777:Tetrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D001713:Biphenyl Compounds; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000077405:Irbesartan