Liver and Renal Physiology in Drug Elimination

Pre-Class Readings: Liver and Renal Physiology Related to Drug Elimination

• Drug elimination involves removal through metabolism (biotransformation) and excretion.
• Liver and kidneys are primary drug-eliminating organs.
• Hydrophilic drugs are excreted by the kidneys.
• Lipophilic drugs are metabolized by the liver into water-soluble forms for kidney excretion or metabolites in bile.

Liver Physiological Functions

• The liver is critical for fat digestion, carbohydrate storage, blood detoxification, and protein production.
• The liver receives dual blood supply:
  • 25% from the hepatic artery (oxygenated blood)
  • 75% from the portal vein (deoxygenated blood rich in nutrients from digestive tract).
• Blood from both sources flows through hepatic sinusoids, lined by endothelial cells and Kupffer cells (phagocytic macrophages).
• The liver produces bile, which aids in fat digestion.
• Efflux transporters may pump drugs into bile.
• The liver is metabolically active; it functions as digestive, endocrine, hematological, and excretory organ
• Digestive: Bile secretion for fat digestion, Processes carbs & proteins from intestines, stores & Processes vitamins & minerals.
• Endocrine: Metabolism of glucocorticoids, mineralocorticoids, sex hormones, and regulates carbohydrate, fat, and protein metabolism.
• Hematologic: Stores blood, removes bilirubin, produces blood clotting factors.
• Excretory: Excretes bile pigment, cholesterol, urea. Detoxifies drugs and foreign substances.

Drug Elimination and Biotransformation

• Drug metabolism in the liver is site- and flow-dependent.
• Enzymes (e.g., CYP enzymes) are responsible for oxidation/reduction reactions (phase I).
• Phase I reactions introduce or expose a functional group on the drug molecule.
• Phase II reactions involve conjugating the drug with another molecule (glucuronidation, sulfation, etc.) making it more water-soluble to be eliminated in bile or urine.
• First-pass effect describes rapid metabolism of a drug by the liver/intestine before reaching systemic circulation.
• Enterohepatic circulation is a cycle where a drug or its metabolite is excreted into bile, reabsorbed and re-enters the system.

Renal Physiological Functions

• Kidneys are located between the 12th thoracic and 3rd lumbar vertebrae.

• Renal blood supply is significant (approximately 25% of cardiac output).

• The functional unit is the nephron.

• Glomerular filtration rate (GFR) is the rate at which blood is filtered by the glomeruli.

• GFR is influenced by blood volume, pressure, and other factors.

• The nephron regulates fluid and electrolyte balance, and removes waste products.

• Kidneys produce erythropoietin (stimulates red blood cell production) and activate Vitamin D.

• Glomerular Filtration: The first step in urine formation. Blood pressure forces water and small solutes from the glomerulus into Bowman's capsule.

• Tubular Reabsorption: The process whereby essential substances (e.g., water, glucose, amino acids) are reabsorbed back into the bloodstream from the filtrate.

• Tubular Secretion: Substances (e.g., waste products, excess ions) are transported from the blood into the filtrate.

• Age, gender, and race can affect drug metabolism and renal function.