Synergism Of Irbesartan And Amolodipine On Blood Pressure And Pharmacokinetics Of Compound Preparation

Hypertension is one of the most common cardiovascular diseases. It alwaysleads to complications of heart, kidney and brain etc. We know that the higher thelevel of blood pressure is, the severer the target organ damages are. Thus, the keypoint of anti-hypertension is to low effectively blood pressure and prevent well organdamages But things are not so simple Howerve high BP level is not the unique factordetermining hypertensive organ damage. Evidences have shown that blood pressurevariability (BPV) is also an important factor determining end organ damage inhypertension. Therefore, decreasing BPV should be considered when blood pressurelevel is controlled. Researches on anti-hypertensive drugs made much progress inrecent years, but the total rate control is still far from optimality. Combination of twoor three antihypertensive drugs gained more and more attention these years for itsadvantages in simplifying dosing regimens, improving patients' compliance,increasing rate control to 70％, decreasing dose-dependent side effects and reducingcost compared to monotherapy. According to the therapeutic principles and trends ofstudies, we mainly studied the synergic effect of combination therapy and thepharmacokinetics of combination. The ingredients in our combination therapy areirbesartan (angiotension receptor 1 antagonist, Irb) and amlodipine (calcium channelblocker, Aml).There are two parts in the present study:1. Possible synergism of Irbesartan and AmlodipineThis part was designed to investigate the possible synergism of Irbesartan andAmlodipine on lowering blooding pressure and BPV, and on organ protection inspontaneously hypertensive rats (SHR).In the acute therapy, sixty-four SHR were randomly divided into 8 groups. Theywere respectively given 0.8％carboxymethylcellulose sodium (control), Irbesartan (50 mg/kg), Amlodipine (0.5, 1, 2 mg/kg) and the combinations of Irbesartan andAmlodipine (50+0.5, 50+1, and 50+2 mg/kg). The drugs were given via a catheterof gastric fistula. Blood pressure was recorded from one hour before drugadministration for 25 hours in conscious freely moving condition of SHR. q value testwas performed to assess the synergism of two antihypertensive drugs on BP and BPVreduction. It was found that combination of Irbsartan and Amlodipine significantlydecreased blood pressure (SBP) and systolic blood pressure variability (SBPV).According to probability sum analysis, it was found that proportion of Irbsartan andAmlodipine=50:1 was the best combination (q=1.23).In long-term therapy, 6 groups were set: Amlodipine (1.0 mg/kg/d), Irbesartan(50mg/kg/d), and the combinations of Irbesartan and Amlodipine (25+0.5, 50+1.0,50+2.0 mg/kg/d). Drugs were mixed into rat chow. The ingredient and content ofdrugs in chow was calculated according to theoretically estimated drug doses andfood consumption previously recorded. The control groups received normal rat chowwithout any drugs. 16 weeks later, BP and BPV were recorded for 5 hours, then therats was weighed and killed by decapitation. The aorta and heart was excised andrinsed in cold physiological saline. Organ damage was estimated by observation ofmorphologic changes. The q value test was performed to assess the synergism of twoantihypertensive drugs on BP and BPV reduction and organ protection. It was foundthat the combination of Irbsartan and Amlodipine at 50+1 mg/kg/d synergized themost optimally.In conclusion, this part clearly demonstrated that the combination of Irbesartanand Amlodipine is synergistic in lowering and stabilizing BP and organ protection.The synergism is greatest when the dose proportion of the two drugs is 50:1.2. Pharmacokinetics of compound preparation of Irbesartan and AmlodipineSix adult healthy beagle dogs in a randomized 2-way crossover study, dividedinto three groups, were given a single oral dose of compound powder of amlodipineand irbesartan (containing 5 mg amlodipine and 250 mg irbesartan), 5 mg amlodipinepowder and 250 mg irbesartan powder respectively. The pharmacokinetics and bioequivalence of amlodipine powder and compound amlodipine and irbesartan(represented by amlodipine), irbesartan powder and compound amlodipine andirbesartan (represented by irbesartan) were compared. The plasma concentrations ofamlodipine and irbesartan were measured by high performance liquidchromatography-electrospray ionization tandem mass spectrometry. No matrix effectwas observed to interfere the peak of amlodipine and irbesartan. The relative recoveryof amlodipine and irbesartan were both above 90％. The relative standard deviation ofinter-day and intra-day of arnlodipine and irbesartan were below 10％and 15％,respectively. The lower limit of quantitation of amlodipine and irbesartan in plasmawere 4.99 ng/ml and 10.01ng/ml, with the linear range 4.99-499.00 ng/ml and10.01-5005.00 ng/ml, respectively. No significant difference appears in thepharmacokinetic parameters between the formulations. The relative bioavailability ofcompound amlodipine and irbesartan (represented by amlodipine) is104.06％±14.36％. The AUC and Cmax between the two formulations, amlodipinepowder and compound amlodipine and irbesartan (represented by amlodipine) arebioequivalent. The relative bioavailability of compound amlodipine and irbesartan(represented by irbesartan) is 99.7％±10.5％. The AUC and Cmax between the twoformulations, irbesartan powder and compound amlodipine and irbesartan(represented by irbesartan) are bioequivalent. The sesults show that the combinationof amlodipine and irbesartan has not influence each other in pharmacokinetics.