Pharmacokinetics Detailed Notes

University:
University of Wolverhampton
Course:
4PY019 | Pharmacy
Academic year:

2024
Views:

286

Pages:

2
Author:

Carisma W.

Pharmacokinetics – Detailed Notes 1. Introduction • Pharmacokinetics (PK): What the body does to the drug (ADME: Absorption, Distribution, Metabolism, Excretion) • Relevance: Determines drug efficacy, dosage, and safety 2. Clinical Endpoints • Measurement of drug amount/concentration in biological fluids over time (usually plasma) • Minimum Toxic Concentration (MTC): Highest concentration before toxicity • Minimum Effective Concentration (MEC): Minimum dose for therapeutic effect • Therapeutic Range: Distance between MEC and MTC • Cmax: Peak plasma concentration • Tmax: Time of peak concentration • AUC (Area Under the Curve): Total drug exposure over time; used to calculate bioavailability • Variability in AUC: Different patients metabolize drugs differently, leading to differing exposure • Half-life (t½): Time for plasma concentration to decrease by half (determined by distribution and elimination) • Pharmacokinetic variability: intrinsic (genetic) or extrinsic (environment, diet) 3. Drug Metabolism • Primary site: Liver • Function: Chemical modification of drugs → metabolites • First-Pass Effect: Oral drugs exposed to liver before systemic circulation • General role: Increase polarity for excretion 3.1 Phase 1 Metabolism • Modifies molecular structure • Oxidation (common): Hydroxylation (-OH addition) • Enzymes: Cytochrome P450 (CYP) • Mechanism: Electron from NADPH → oxygen-bound heme species → radical formation → insertion of oxygen into C-H bond → regenerates CYP 3.2 Phase 2 Metabolism • Conjugation of polar groups to metabolites • Common reactions: glucuronidation, sulfation • Identified via mass spectrometry • Majority carried out by CYP enzymes in liver 3.3 Other Considerations • Different enantiomers metabolized at different rates 1 • Lipophilic compounds more likely to bind CYP → metabolized faster • Phase 1 metabolites more polar → less likely to bind proteins → slower further metabolism • Reducing metabolism: block CYP binding sites or reduce lipophilicity (log P) • Example: Fluorine blocking CYP binding site increases half-life/shelf-life 4. Drug-Protein Binding • Kd (dissociation constant): Measures affinity of ligand for protein (low Kd = high affinity) • Favourable binding: Balance of enthalpic and entropic contributions • When ligand binds: • Enthalpic: Loss of ligand-water bonding, gain of protein-ligand interactions • Entropic: Loss of conformational flexibility • Loss of interactions: • Enthalpic: ligand-water and protein-water interactions • Entropic: conformational flexibility • Gain of interactions: • Enthalpic: formation of bonds with protein • Entropic: release of water to bulk • Lipophilic molecules: Binding driven mainly by entropy (water desolvation) • Polar molecules: Binding driven mainly by enthalpy (specific bonding) • Lipophilic compounds more likely metabolized by CYP due to entropic binding • Lipophilicity = best predictor for CYP binding and metabolism likelihood 5. Summary • PK crucial for understanding dose, efficacy, and safety • Drug metabolism is majorly liver-based (CYP-mediated) • Binding properties influence metabolism and half-life • Understanding chemical/physical properties of drugs aids design of more effective and longerlasting therapies 2