Elimination encompasses all processes that remove drug from the body, including both metabolism and excretion. While metabolism chemically transforms the drug into more polar metabolites, excretion is the physical removal of drug and metabolites from the body. The kidney is the primary organ of excretion, but the liver, lungs, sweat glands, and mammary glands also contribute. Understanding elimination pathways is essential for predicting drug duration of action, designing appropriate dosing regimens, and adjusting therapy in patients with organ dysfunction.
Renal Excretion
The kidney eliminates drugs through three fundamental processes: glomerular filtration, tubular secretion, and tubular reabsorption. Glomerular filtration is a passive process in which drug molecules small enough to pass through the glomerular capillary pores enter the tubular lumen. Only unbound drug is filtered, so protein binding limits the amount available for glomerular filtration. The glomerular filtration rate, approximately 120 mL per minute in healthy adults, determines the rate at which filtrate is presented to the tubules.
Tubular secretion is an active transport process that moves drugs from the peritubular capillaries into the tubular lumen. Two distinct transport systems exist: one for organic anions and one for organic cations. These systems can secrete drugs against a concentration gradient and are saturable, allowing for drug-drug interactions. Probenecid, for example, inhibits the organic anion transporter, reducing the secretion of penicillin and prolonging its half-life, a strategy once used therapeutically.
Tubular reabsorption is the passive diffusion of drug from the tubular lumen back into the bloodstream. As water is reabsorbed along the nephron, the concentration of drug in the tubular fluid rises, creating a concentration gradient favoring reabsorption. Only the unionized, lipid-soluble form of the drug is reabsorbed, making urinary pH a critical determinant of drug excretion. Manipulating urinary pH can enhance elimination of certain drugs, as in the use of sodium bicarbonate to alkalinize the urine and increase the excretion of weak acids such as phenobarbital.
Biliary Excretion and Enterohepatic Circulation
Drugs and their metabolites can be excreted into bile by active transport systems in the hepatocyte canalicular membrane. Biliary excretion is particularly important for drugs with molecular weights exceeding 500 daltons and for conjugated metabolites. Once excreted into bile, the drug enters the duodenum and may be eliminated in the feces. However, gut bacteria often hydrolyze glucuronide conjugates, releasing the parent drug, which can then be reabsorbed in a process known as enterohepatic circulation. This cycle prolongs the presence of the drug in the body and can contribute to sustained drug levels.
Pulmonary and Other Routes of Excretion
Pulmonary excretion is the primary elimination route for volatile and gaseous agents such as anesthetics. The rate of pulmonary excretion depends on the solubility of the agent in blood and the rate of respiration. Highly soluble agents are eliminated more slowly because they partition extensively from blood into tissues. Other minor routes of excretion include sweat, saliva, tears, and breast milk. Excretion into breast milk is clinically important because it exposes nursing infants to maternally administered drugs.
Elimination Half-Life and Clearance
The elimination half-life (t½) is the time required for the plasma concentration of a drug to decrease by 50%. Half-life depends on both clearance and volume of distribution according to the relationship t½ = 0.693 × Vd / CL. Clearance describes the volume of plasma from which drug is completely removed per unit time and is the most important parameter for determining maintenance dose requirements. While half-life determines the time required to reach steady state and the duration of drug action after discontinuation, it is clearance that governs the average steady-state concentration during chronic dosing. Together, these parameters provide a complete picture of drug elimination kinetics and guide the rational design of dosing regimens.
