Drugs are eliminated from the body either unchanged by the process of excretion or converted to metabolites (see Chapters 2 and 3). Excretory organs, the lung excluded, eliminate polar compounds more efficiently than substances with high lipid solubility. Lipid-soluble drugs thus are not readily eliminated until they are metabolized to more polar compounds.
The kidney is the most important organ for excreting drugs and their metabolites. Substances excreted in the feces are principally unabsorbed orally ingested drugs or drug metabolites excreted either in the bile or secreted directly into the intestinal tract and not reabsorbed. Excretion of drugs in breast milk is important not because of the amounts eliminated, but because the excreted drugs will have unwanted pharmacological effects in the nursing infant. Excretion from the lung is important mainly for the elimination of anesthetic gases (see Chapter 13).
RENAL EXCRETION Excretion of drugs and metabolites in the urine involves three distinct processes: glomerular filtration, active tubular secretion, and passive tubular reabsorption. Changes in overall renal function generally affect all three processes to a similar extent. In neonates, renal function is low compared with body mass but matures rapidly within the first few months after birth. During adulthood, there is a slow decline in renal function, -1% per year, so that in elderly patients a substantial degree of functional impairment may be present.
The amount of drug entering the tubular lumen by filtration depends on the glomerular filtration rate and the extent of plasma binding of the drug; only unbound drug is filtered. In the proximal renal tubule, active, carrier-mediated tubular secretion also may add drug to the tubular fluid. Transporters such as P-glycoprotein and the multidrug-resistance-associated protein type 2 (MRP2), localized in the apical brush-border membrane, are responsible for the secretion of amphi-pathic anions and conjugated metabolites (e.g., glucuronides, sulfates, and glutathione adducts), respectively (see Chapters 2 and 3). Adenosine triphosphate (ATP)-binding cassette (ABC) transporters that are more selective for organic cationic drugs are involved in the secretion of organic bases. Membrane transporters, mainly located in the distal renal tubule, also are responsible for any active reabsorption of drug from the tubular lumen back into the systemic circulation.
In the proximal and distal tubules, the nonionized forms of weak acids and bases undergo net passive reabsorption. The concentration gradient for back-diffusion is created by the reabsorption of water with Na+ and other inorganic ions. Since the tubular cells are less permeable to the ionized forms of weak electrolytes, passive reabsorption of these substances depends on the pH. When the tubular urine is made more alkaline, weak acids are largely ionized and thus are excreted more rapidly and to a greater extent. When the tubular urine is made more acidic, the fraction of drug ionized is reduced, and excretion is likewise reduced. Alkalinization and acidification of the urine have the opposite effects on the excretion of weak bases. In the treatment of drug poisoning, the excretion of some drugs can be hastened by appropriate alkalinization or acidification of the urine (see Chapter 64).
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