Biopharmaceutics and Pharmacokinetics Module 7: Drug Elimination PDF

BIOPHARMACEUTICS AND PHARMACOKINETICS MODULE 7: DRUG ELIMINATION AND CLEARANCE I. INTRODUCTION Drug elimination is usually divided into two major components: excretion and biotransformation. Drug excretion is the removal of the intact drug. Nonvolatile and polar drugs are excrete...

BIOPHARMACEUTICS AND PHARMACOKINETICS MODULE 7: DRUG ELIMINATION AND CLEARANCE I. INTRODUCTION Drug elimination is usually divided into two major components: excretion and biotransformation. Drug excretion is the removal of the intact drug. Nonvolatile and polar drugs are excreted mainly by renal excretion, a process in which the drug passes through the kidney to the bladder and ultimately into the urine. Other pathways for drug excretion may include the excretion of drug into bile, sweat, saliva, milk (via lactation), or other body fluids. Volatile drugs, such as gaseous anesthetics, alcohol, or drugs with high volatility, are excreted via the lungs into expired air. Drug clearance is a pharmacokinetic term for describing drug elimination from the body without identifying the mechanism of the process. Drug clearance (also called body clearance or total body clearance, and abbreviated as Cl or ClT) considers the entire body as a single drug-eliminating system from which many unidentified elimination processes may occur. Instead of describing the drug elimina- tion rate in terms of amount of drug removed per unit of time (eg, mg/h), drug clearance is described in terms of volume of fluid removed from the drug per unit of time (eg, L/h). II. ANATOMY AND PHYSIOLOGY OF THE KIDNEY The kidney is the main excretory organ for the removal of metabolic waste products and plays a major role in maintaining the normal fluid volume and electrolyte composition in the body. To maintain salt and water balance, the kidney excretes excess electrolytes, water, and waste products while con- serving solutes necessary for proper body function. The kidneys are located in the peritoneal cavity. The outer zone of the kidney is called the cortex, and the inner region is called the medulla. The nephrons are the basic functional units, collectively responsible for the removal of metabolic waste and the maintenance of water and electrolyte balance. Each kidney contains 1-1.5 million nephrons. The glomerulus of each nephron starts in the cortex. Cortical nephrons have short loops of Henle that remain exclusively in the cortex; juxtamedullary nephrons have long loops of Henle that extend into the medulla. The longer loops of Henle allow for a greater ability of the nephron to reabsorb water, thereby producing more concentrated urine. III. RENAL DRUG EXCRETION Renal excretion is a major route of elimination for many drugs. Drugs that are nonvolatile, are water soluble, have a low molecular weight (MW), or are slowly biotransformed by the liver are eliminated by renal excretion. The processes by which a drug is excreted via the kidneys may include any combination of glomerular filtration, active tubular secretion, and tubular reabsorption. NDCorcinoRPh2024 Page 1 of 3 Glomerular filtration is a unidirectional process that occurs for most small molecules (MW < 500), including undissociated (nonionized) and dissociated (ionized) drugs. Protein-bound drugs behave as large molecules and do not get filtered at the glomerulus. The major driving force for glomerular filtration is the hydrostatic pressure within the glomerular capillaries. The kidneys receive a large blood supply (approximately 25% of the cardiac output) via the renal artery, with very little decrease in the hydrostatic pressure. Glomerular filtration of drugs is directly related to the free or nonprotein-bound drug concen- tration in the plasma. As the free drug concentration in the plasma increases, the glomerular filtration for the drug increases proportionately, thus increasing renal drug clearance for some drugs. Active tubular secretion is an active transport process. As such, active renal secretion is a carrier- mediated system that requires energy input, because the drug is transported against a concentration gradient. The carrier system is capacity limited and may be saturated. Drugs with similar structures may compete for the same carrier system. Active tubular secretion rate is dependent on RPF. For a drug that is excreted solely by glomerular filtration, the elimination half-life may change markedly in accordance with the binding affinity of the drug for plasma proteins. In contrast, drug protein binding has very little effect on the elimination half-life of the drug excreted mostly by active secretion. Because drug protein binding is reversible, drug bound to plasma protein rapidly dissociates as free drug is secreted by the kidneys. Tubular reabsorption occurs after the drug is filtered through the glomerulus and can be an active or a passive process involving transporting back into the plasma. IV. BILIARY EXCRETION OF DRUGS The biliary system of the liver is an important system for the secretion of bile and the excretion of drugs. Anatomically, the intrahepatic bile ducts join outside the liver to form the common hepatic duct. The bile that enters the gallbladder becomes highly concentrated. The hepatic duct, containing hepatic bile, joins the cystic duct that drains the gallbladder to form the common bile duct. The common bile duct then empties into the duodenum. Bile consists primarily of water, bile salts, bile pigments, electrolytes, and, to a lesser extent, cholesterol and fatty acids. The hepatic cells lining the bile canaliculi are responsible for the production of bile. The production of bile appears to be an active secretion process. Drugs that are excreted mainly in the bile have molecular weights in excess of 500. Drugs with molecular weights between 300 and 500 are excreted both in urine and in bile. NDCorcinoRPh2024 Page 2 of 3 Enterohepatic Circulation A drug or its metabolite is secreted into bile and upon contraction of the gallbladder is excreted into the duodenum via the common bile duct. Subsequently, the drug or its metabolite may be excreted into the feces or the drug may be reabsorbed and become systemically available. The cycle in which the drug is absorbed, excreted into the bile, and reabsorbed is known as enterohepatic circulation. Significance of Biliary Excretion When a drug appears in the feces after oral administration, it is difficult to determine whether this presence of drug is due to biliary excretion or incomplete absorption. If the drug is given parenterally and then observed in the feces, one can conclude that some of the drug was excreted in the bile. Because drug secretion into bile is an active process, this process can be saturated with high drug concentrations. Moreover, other drugs may compete for the same carrier system. Drugs that undergo enterohepatic circulation sometimes show a small secondary peak in the plasma drug–concentration curve. The first peak occurs as the drug in the GI tract is depleted; a small secondary peak then emerges as biliary-excreted drug is reabsorbed. NDCorcinoRPh2024 Page 3 of 3