Determinants of the pharmacokinetics of antithrombotic drugs

This review describes a variety of factors which determine the pharmacokinetics of antithrombotic drugs, viz., elimination by hepatic and/or renal clearance, plasma protein binding and drug disposition in the geriatric population. An understanding of biotransformation of acetylsalicylic acid and sulfinpyrazone is critical to understanding their usefulness as antithrombotic agents. Acetylsalicylic acid is rapidly hydrolysed to salicylic acid in the body and the latter may be eliminated by five different routes. Two of the biotransformation processes involving salicylic acid are readily saturable. For this reason, salicylate concentration increases more than proportionately with an increase in dose. Acetylsalicylic acid, but not salicylic acid, acetylates cyclo-oxygenase resulting in its inactivation. It is important in pharmacokinetic studies to measure plasma levels of both acetylsalicylic acid and salicylic acid. Biotransformation of sulfinpyrazone involves oxidation to the sulfone and reduction to the sulfide. The sulfide has marked antiplatelet activity. Dipyridamole undergoes hepatic biotransformation to a monoglucuronide which is eliminated by biliary and fecal excretion. Sulfinpyrazone, dipyridamole and salicylic acid are highly bound to plasma proteins. Since binding diminishes with age, one must expect therapeutic and toxic effects at lower plasma drug concentrations in the geriatric population. Other factors to be considered in the geriatric group are altered distribution, diminished glomerular filtration rate, and diminished oxidative biotransformation.