In-Vitro Relationship between Protein-Binding and Free Drug Concentrations of a Water-Soluble Selective Beta-Adrenoreceptor Antagonist (Atenolol) and Its Interaction with Arsenic

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The pharmacokinetic properties of exogenous and endogenous compounds can be influenced by reversible binding to human serum albumin (HSA), which is thought to be one of the primary determinants of the pharmacokinetic properties of drugs (1-4). Therefore, when evaluating interactions among drugs, it is important to be aware of possible identities of their binding sites on the protein because any alteration in drug-binding to HSA, including binding of the antihypertensive drugs, could lead to a change in pharmacokinetic properties. Human serum albumin can be immobilized in spherical, macroporous microparticles of polyacrylamide of about 1 [micro]m in diameter with retention of its native properties (5). Results of different experiments suggest that human serum albumin has a limited number of binding sites (4,6,7). On the basis of the probe-displacement method, there are at least three relatively-high specific drug-binding sites on the HSA molecule. These sites, commonly called warfarin, benzodiazepine, and digoxin-binding sites, are also denoted as Site I, Site II, and Site III respectively (4,8,9). It has been shown that diazepam, digitoxin, and warfarin independently bind to albumin and can conveniently be used as markers of three separate, discrete binding sites on albumin (5). Since numbers of protein-binding sites are limited, competition will exist between two drugs, and the drug with higher affinity will displace the other, causing increased free drug concentration leading to higher toxicity (10-12).

Plasma protein-binding properties are related to plasma clearance, elimination half-life, apparent volume of the distribvution, and area under the curve. The beta-blockers comprise a group of drugs that are mostly used in treating cardiovascular disorders, such as hypertension, cardiac arrhythmias, or ischemic heart diseases. As a class, the beta-blockers are quite diverse from a pharmacokinetic perspective as they display a high range of values in plasma protein-binding, percentage of drug eliminated by metabolism, or unchanged in the urine and in hepatic excretion ratio. In clinical practice, the beta-adrenergic antagonists are an extremely important class of drugs due to their high extent of use. The non-selective beta-blockers, including propranolol, oxprenolol, pindolol, nadolol, timolol, and labetalol each antagonize both [[beta].sub.1] and [[beta[.sub.2]-adrenergic receptors (ARs). The selective antagonists, including metoprolol, atenolol, esmelol, and acebutolol, have much greater binding-affinity for the [[beta].sub.1]-AR. The selective beta-blockers are normally indicated for patients in whom [[beta].sub.2]-receptor antagonism might associate with an increased risk of adverse effects. Such patients include those with asthma, or diabetes, or with peripheral vascular diseases, or Raynaud's disease (13). Of all known beta-adrenolytics, propranolol has the highest lipohilicity and can cross the blood brain barrier (BBB) whereas atenolol is a highly hydrophilic drug (partition coefficient of 0.02) (14). Hydrophilic beta-blockers, such as atenolol, are advantageous in patients who suffer from central nervous side-effects (sleep disturbances, psychosis, depression, and hallucination) during therapy with lipophilic drugs (13).

Lipophilic drugs, such as propranolol, are extensively metabolized by the liver while hydrophilic beta-blockers, including atenolol, are predominantly excreted through the kidney (Table 1) (15,16). In patients with normal renal function, the atenolol half-life was calculated to be about six hours following single 100-mg oral dose. This value increased markedly in patients with renal insufficiency, and the blood clearance of atenolol was found to have a significant correlation with the glomerular filtration rate (17).

Approximately 91-96% of propranolol can be bound to serum albumin or other proteins, mainly to [[beta].sub.1]-acid glycoprotein and lipoproteins (18). …