Abstract
The present experiment shows how clinically two important drugs, amlodipine besylate (AB) and benazepril hydrochloride (BH), bind with serum protein and their mutual effect to displace each other from their binding sites. Binding chemistry of amlodipine besylate and and benazepril hydrochloride to bovine serum albumin (BSA) was evaluated by equilibrium dialysis method at pH 7.4 and 37°C temperature. The binding of these two drugs have been characterized by two sets of association constant: high affinity constant (K1) with low capacity (n1) and low affinity association (k2) constant with high capacity (n2). The non-linear curve of the scatchard plot suggested high affinity binding sites (K1 = 8.47x105 M-1, n1=1.9) and low affinity binding sites (K2 = 0.33 x105 M-1 , n2=11.7) for amlodipine besylate. On the other hand for benazepril hydrochloride high affinity constant (K1) was 14 x105 M-1 (n1 =1) and low affinity constant (K2) was 0.31 x105 M-1 (n2 = 16 ). Site specific probe displacement data showed that amlodipine besylate primarily binds to site I (the warfarin sodium site), while the low affinity site of this drug is site II (diazepam site) on BSA. On the other hand, benazepril hydrochloride primarily binds to site II (diazepam site) on BSA. The investigated drugs compete for different site (site-I amlodipine besylate and site-II benazepril hydrochloride) and they do not displace each other on bovine serum albumin, hence concurrent administration of these two drugs will not alter the therapeutic efficacy of each other and co-administered of these two drugs can be effective as a combination dosage form in the management of hypertension.
Highlights
Nowadays, the most effective way to manage cardiovascular problems is combination therapy
The investigated drugs compete for different site and they do not displace each other from bovine serum albumin, concurrent administration of these two drugs will not alter the therapeutic efficacy of each other and co-administered of these two drugs can be effective as a combination therapy in the management of hypertension
Determining association constant and number of binding sites Drug-protein binding are mainly of two types –strong affinity binding to a smaller number of sites and weak affinity binding to a large number of sites
Summary
The most effective way to manage cardiovascular problems is combination therapy. The most outstanding property of albumin is its ability to bind reversibly with different. Efficacy as well as toxic profile of drug depends largely on its ability to bind with serum protein. The more binding of drug with plasma protein indicates the less free drug in the blood. It is generally assumed that free drug concentration in the blood is responsible for its action on biological system. The present study has centered mainly on the binding chemistry of amlodipine besylate (calcium channel blocker) and benazepril hydrochloride (angiotensin converting enzyme inhibitor) to BSA. To observe binding chemistry of amlodipine besylate and benazepril hydrochloride on BSA, the association constants as well as the binding sites to Bovine Serum Albumin (BSA) were calculated by scatchard analysis (Scatchard, 1949) at pH 7.4 and 37°C. In this study BSA was used in lieu of HAS (human serum albumin), because of its structural similarity with HSA, low cost and easy availability
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