Farmacocinética: METABOLISMO de fármacos

Metabolism of Drugs: Key Concepts

Introduction to Drug Metabolism

• Enrique García Ball introduces the topic of drug metabolism, emphasizing its importance in pharmacokinetics, which studies how drugs transform within the body.

The Role of the Liver in Drug Metabolism

• The liver is identified as the primary organ for drug biotransformation. Oral medications undergo "first-pass metabolism," where they are absorbed through the digestive system and enter circulation via the mesenteric venous system before reaching the liver.

• While the liver is crucial, other organs like lungs and intestinal epithelium can also participate in metabolism. However, hepatic metabolism remains predominant due to significant blood flow (1.1 liters per minute from venous sources).

Phases of Drug Metabolism

• Drug metabolism occurs in two phases: Phase 1 involves oxidation, reduction, and hydrolysis reactions that convert drugs into less polar compounds or activate prodrugs.

• Phase 2 consists of conjugation reactions (e.g., acetylation, glucuronidation), producing highly polar products that are typically inactive.

Cytochrome P450 Enzymes

• Cytochrome P450 enzymes play a vital role in Phase 1 reactions; CYP3A4 is highlighted as metabolizing over 50% of all human-used drugs.

• Genetic polymorphisms in cytochromes can lead to varied drug responses among individuals, a focus area for pharmacogenetics.

Interactions with Cytochrome P450

• Drugs can act as substrates (metabolized by cytochromes), inducers (increase enzyme activity), or inhibitors (decrease enzyme activity). Understanding these interactions is critical for managing polypharmacy.

• An example illustrates how ibuprofen acts as a substrate for CYP2C9; if taken with verapamil (an inhibitor), ibuprofen's metabolism slows down significantly.

Clinical Implications of Drug Interactions

• Another example shows rifampicin acting as an inducer when taken with ibuprofen, leading to faster metabolism due to increased CYP2C9 synthesis.

Metabolism of Statins and Drug Interactions

Overview of Statin Metabolism

• Statins are often taken in combination with other medications, such as dexamethasone, which can induce cytochrome P450 enzymes (CYP3A4), leading to faster metabolism of statins.

• Phase 2 metabolism involves various enzymes that facilitate processes like glucuronidation and conjugation with glutathione, crucial for drug activity termination.

Clinical Implications of Enzyme Deficiencies

• Patients with Gilbert's syndrome, affecting about 10% of the population, have a deficiency in the enzyme glucuronosyltransferase due to a genetic mutation. This can complicate drug metabolism and increase adverse effects.