Pharmacokinetics Basics Lecture Notes

Pharmacokinetics Study of drug movement in the body Absorption Transfer of drug from administration site to circulation Distribution Transport of drug within the body Metabolism Chemical alteration of drug in the body Excretion Removal of drug or its metabolites from the body ADME Acronym for absorption, distribution, metabolism, excretion Bioavailability Fraction of administered drug reaching systemic circulation Volume of Distribution (V) Theoretical volume drug is uniformly distributed First Pass Effect Metabolism of drug before reaching general circulation Enteral Route of drug administration involving GI tract Parenteral Route of drug administration not involving GI tract Intravenous (IV) Route of drug administration directly into the vein Sublingual Route of drug administration bypassing portal vein Rectal Route of drug administration partially bypassing portal vein Topical Route of drug administration on body surfaces Bioequivalence Comparison of different drug formulations AUC Area under the plasma concentration vs. time curve Cmax 1/5 Maximum concentration of drug in plasma Tmax Time taken to reach maximum drug concentration MEC Minimum effective concentration of a drug MTC/MSC Maximum therapeutic/safe concentration of a drug Dissolution Process of drug moving from solid state into solution Deaggregation Process of breaking down drug aggregates Stomach pH 1-2; initial site of digestion Duodenum pH 5-6; receives chyme from stomach Jejunum/Ileum pH 7; major site of absorption Colon pH 6.5; site of water reabsorption Transverse Colon Part of the large intestine Ascending Colon Part of the large intestine Descending Colon Part of the large intestine Appendix Small, tube-like structure attached to the large intestine Absorption from the Small Intestine Small intestine is the major drug absorption site due to surface area modifications Luminal Folds 3-fold increase in surface area Villi 10-fold increase in surface area Microvilli 20-fold increase in surface area Intestinal Villus Structure composed of absorptive enterocytes, lamina propria, and goblet cells Crypts Invaginations in the intestinal wall Microvilli & Tight Junctions 2/5 Finger-like projections on epithelial cells forming the brush border membrane Transcellular Absorption Major route of drug absorption through the cell membrane Phospholipid Head Part of the cell membrane structure Lipophilic Tail Part of the cell membrane structure Protein Part of the cell membrane structure LogP Partition coefficient measuring drug's lipophilicity pKa Ionization constant reflecting drug's tendency to donate a proton Permeation and Hydrogen Bonding Greater hydrogen bonds lead to less likely absorption Rule of 5 Criteria for good absorption: MW<500, logP<5, H-bond donors<5, H-bond acceptors<10 Paracellular Absorption Drug passage through cell gaps, requires low MW (<300) and water solubility, limited from colon Active Transport (Uptake) Energy-dependent drug transport through membrane by specific transporter, not passive Active Transport - Efflux P-glycoprotein acts as barrier to oral absorption, found in various cell surfaces Volume of Distribution (Vd) Hypothetical volume for drug distribution, not a real 'volume', used to define dose for specific plasma concentration Body Fluid Compartments Major compartments: plasma, interstitial fluid, intracellular fluid, transcellular fluid, and fat Plasma Protein Binding (PPB) Drugs binding to blood proteins, affects drug distribution and potential drug-drug interactions 3/5 Barriers to Drug Distribution Blood-brain barrier and placenta restrict drug entry, affected by drug lipophilicity and size Rate of Distribution Influenced by membrane permeability and blood perfusion, affects drug distribution extent Salt Factor Adjustment factor for drug doses administered as salts to account for the mass of the parent drug Drug Elimination Proportional to drug concentration in body fluids, influenced by volume of distribution Varying volumes of distribution for differDrug A, B, and C Volume of Distribution ent drugs, influenced by drug characteristics and physiology Pores between cells Larger in dog than in rat and man, affecting paracellular absorption Active Transport - Saturation Unlike passive absorption, can be saturated by high drug concentrations Plasma Protein Binding (PPB) Levels Different levels (negligible, moderate, high, very high) affect drug distribution and activity Protein Binding and Drug Effect Free drug is pharmacologically active, while protein-bound drug is not available for effect or distribution Acids bind to albumin, bases bind to alPlasma Protein Binding (PPB) Mechapha-1 acid glycoprotein, influenced by nism drug lipophilicity Drug Distribution Patterns Varied distribution patterns in the body, influenced by drug characteristics and tissue permeability Plasma Protein Binding (PPB) and Drug-Drug Interactions Competition for protein binding can alter drug concentration and lead to interactions, especially for drugs with narrow therapeutic index 4/5 Reflects drug excretion, with highest Drug Distribution in Body Fluid Compartconcentrations in kidney, liver, and intesments tine Factors Affecting Drug Distribution Influenced by membrane permeability, blood perfusion, lipophilicity, pKa, protein binding, and size Varied distribution in different body parts Drug Distribution in Body after IV Dose over time, reflecting drug excretion and tissue permeability Used to calculate loading dose for a speVolume of Distribution (Vd) Calculation cific blood concentration, influenced by drug characteristics Drug Distribution in Specific Tissues Some drugs concentrate in specific tissues, influencing their site of action and potential side effects Reflects drug excretion and permeation, Drug Distribution and Body Fluid Comwith varied concentrations in different partments compartments Drug Distribution in Brain and CSF Restricted to lipid-soluble drugs, influenced by blood-brain barrier integrity Drug Distribution in Placenta Allows passage of lipid and some water-soluble drugs, affected by placental enzymes 5/5