Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME) PDF

# Fundamentals in Pki (i) Define & explain the PK processes of absorption, distribution, metabolism & excretion of drug after administration. ## Absorption * **Extravascular administration:** systemic administration occurs when the unchanged drug proceeds from the site of administration to the si...

# Fundamentals in Pki (i) Define & explain the PK processes of absorption, distribution, metabolism & excretion of drug after administration. ## Absorption * **Extravascular administration:** systemic administration occurs when the unchanged drug proceeds from the site of administration to the site of measurement (usually plasma in arm vein), e.g. oral absorption. * **In blood circulation:** blood drug concentration is relatively the same, meaning systemic absorption is achieved. * **Intestinal absorption ≠ systemic absorption** * Leads to metabolism * Biliary excretion ## Distribution * After systemic absorption, drug is distributed via systemic circulation to various tissues and organs in the body, such as cell-to-cell and through bile. * The rate and extent of distribution may differ for different sites. ## Metabolism & Excretion * Our biological system is an "open-system" where drug is eliminated. * Elimination is an irreversible loss of drugs from the site of measurement. * **Two principal organs**: * **Liver:** metabolism: Conversion of one chemical species to another. * **Kidney:** excretion: Irreversible loss of chemically unchanged drug. ## ADME Processes * A drug enters systemic circulation, gets distributed, metabolized, and excreted. * These processes don't happen in succession. * They occur simultaneously with some processes predominating over another, resulting in a final observed exposure-time profile. * This relates to the unchanged parent drug. ## Disposition **Systemic absorption (A)** **BLOOD** **Rest of body** **(D) Distribution** **Meta bolism (M) + Excretion (E)** * Distinguishing between elimination & distribution as a cause for a decline in plasma drug concentration is difficult. * This represents the irreversible loss of drug from the site of measurement. ## (ii) Describe the factors that affect drug movement across a membrane for absorption & Distribution * Drugs are formulated in different dosage forms for administration. * **Permeability across the membrane relates to drug in solution (solvated chemical entity):** * **Drug Transport** * **Passive Transcellular:** Move from one side to another across the phospholipid bilayer. * **Drug must be in solution before it can cross the membrane.** * **Drug must be "free".** * **Drug transport is bi-directional.** * **Passive Diffusion (most common)** * **Carrier - Mediated Transport** * **Passive Facilitated Diffusion - equilibrating transporters**: * **Don't require energy** - move substrates down the concentration gradient until unbound. * **Concentration is equal on both sides at equilibrium.** * **Transport maximum, substrate specific, and can be inhibited** * **Active transport - concentrating transporters**: * **ATP-dependent**: Can move substrates opposing the concentration gradient. * **Directional:** Influx (uptake) or efflux transporters. * **There are many different transporters in multiple organs (GIT, kidneys, liver, brain, etc.)** * **Important for drugs with physiochemical properties that may not favour quick passive diffusion:** * **Plays a role on whether drugs get to the tissues.** * **Facilitated transcellular transporter.** ## Factors Affecting Drug Movement Across Membranes ### Physiochemical 1. **Size:** Permeability drops when size increases. * Gut permeability drops for molecules with MW > 500g/mol. 2. **Lipophilicity (LogP):** * LogP is measured by the n-octanol/water partition coefficient. * More lipophilic, better the permeability, poorer aqueous solubility. 3. **Charge:** Charged molecules move slower across membranes. * Most drugs are weak acids or weak bases - exist in solution as an equilibrium of ionized & unionized forms. * Dependent on physiological pH & pKa. 4. **Solubility:** ### Physiological 1. **Membrane porosity:** Endothelial membranes have different porosities. * **Brain:** Tight junctions. * **Renal glomerulus:** Fenestrated, permeable to molecules up to 5000g/mol. * **Liver sinusoids:** Leaky. * **Blood - Brain Barrier:** * Very tight junctions, presence of efflux transporters (MDR1). * As lipophilicity increases, blood-brain barrier permeability increases. * Vinblastine & Vincristine * Greater lipophilicity but low permeability. * Moderately large (811 and 825g/mol). * Substrates of efflux transporters that pump drug out. 2. **Membrane thickness:** * **Involvement of transporters:** * **Blood Capillaries (except testes, placenta, CNS):** Transport through membranes is independent of lipophilicity, charge or molecular size (up to ~ 500g/mol). * **Renal glomerulus:** * **Nasal mucosa:** * **Buccal mucosa:** * **Gastrointestinal tract:** * **Lung:** * **Hepatocytes:** * **Renal tubule:** * **Blood-Brain Barrier:** Transport affected by lipophilicity, charge and molecular size. Nasal mucosa is more porous than GIT. Transport highly dependent on lipophilicity, charge, and molecular size. ## (iii) Discuss the factors that affect bioavailability * Oral systemic bioavailability is the first primary PK parameter (F). * Drugs are most commonly administered orally. * **F_F:** Fraction that enters intestinal tissues. * Neither lost in the feces nor decomposed in the lumen. * **F_G:** Fraction that reaches portal vein. * Escapes destruction within the walls of GIT. * **F_H:** Fraction that reaches liver AND escapes liver extraction. * "Drug metabolized by drug metabolizing enzymes in GIT (e.g. CYP450)". * **Oral systemic bioavailability is the fraction of an orally administered drug that reaches systemic circulation:** **F = F_F × F_G × F_H** ### Factors - **Metabolism during passage across the intestinal wall and through the liver reduces the amount of drug reaching systemic circulation.** - **"First-Pass Metabolism"** - Loss of drug can be: * **Enzymatic or non-enzymatic** * **Occur within the gut lumen or in the intestinal epithelium other than the liver** - **Adsorption:** * To charcoal, holds drug in GIT. * **Efflux transporters:** reduces absorption of drug (sumatriptan) * **"First-pass effect":** * **Hydrolysis (acid):** Loss of activity, product inactive (Penicillin G & Erythromycin). * **Digoxin:** Products have variable activity. ## (iv) Explain the concepts of apparent volume of drug distribution and appreciate its clinical applicants * If 10mg drug is to be administered, apparent volume = 5L. * **Body water & compartments:** * **Intracellular:** * Cells * V_c = 3L * **Extracellular:** * Interstitial space * V_E = 12L * **Extravascular:** * V_R = 27L * **Intravascular:** * Plasma * V_p = 3L * **DRUG:** * **i.v.** * **Oral** * **Exhale** * **Inhale** * **GIT** * **Liver** * **Feces** * **Bile** * **i.m.** * **S.C** * **Topical** * **Lungs** * **Muscle** * **Blood** * **Skin** * **Kidney** * **Urine** * **Besides dissolving in only body water, drug may also distribute & bind to plasma & tissue proteins, fats, bone.** * **By binding to tissues, decreases drug volume in blood.** * **60% of body weight or 42L in a 70kg man** * **Apparent volume of distribution is the second primary PK parameter.** * This relates the amount of drug in the body to the concentration of drug (C) in blood or plasma. * **V = amount of drug in body / C** * **V may be defined with respect to blood, plasma or water (unbound drug), depending on the concentration used in equation.** * **Drug concentrations in the different biological matrices may be different (Cb, Cp or Cu), therefore V ≠ V_b ≠ V_p.** ## Clinical Applications * **We use the apparent volume of distribution to obtain distribution characteristics of a drug.** * Each drug has a V value determined from clinical PK studies. * We can appreciate where a drug is mostly located. * Protein drugs have V close to plasma volume due to their large molecular size (unable to cross membrane barriers to distribute to tissues). * Basic compounds tend to have larger V than acidic drugs: * Due to protein binding. ## (V) Explain key concepts related to drug-protein binding interactions ### Unbound Fraction * **Blood/Plasma:** * **Independent of unbound fraction (f_u):** (independent of concentration). * **Differing affinity:** * **f_ub = C_u / C_t** * **Tissues (Muscles, fats, liver, brain, etc):** * **f_ur = C_u / C_t** * **Cannot predict f_ut from f_ub or vice versa.** * **Protein-bound drug:** * **Free/unbound drug:** * **Drug bound to RBCs** * **If f_u is a constant, C is a good measure of C_u change.** * **f_u ranges from 0-1, greater f_u, less protein binding.** * **f_u is a variable that impacts V and clearance (CL) since only free drug can be distributed or eliminated.** * **A change in f_u alters primary PK parameters and affects the overall disposition of drug in the body.** ### Equilibrium * **Consider various equilibria** 1. **Bound - unbound drug in plasma blood** 2. **Bound - unbound drug in tissue** 3. **Equilibrium between blood and tissue compartments** ### Drug Binding Plasma Proteins * The different proteins have different abundance, drug selectivity, and binding affinity. * **Albumin is the most abundant.** | Protein | MW (kDa) | Normal Conc. (g/dL) | Drug | Selectivity | Affinity (K_d) | |---|---|---|---|---|---| | Albumin | 67 | 3.5 - 5.0 (500-700 µM) | Wide | mM | μM | | α-Acid glycoprotein | 37 - 54 | 0.001 - 0.007 (0.6 - 1.4 µM) | Lipophilic amines (basic) | Variable | mM | | Lipoproteins | 200 - 2,400 | 0.04 - 0.1 (9 - 23 µM) | Lipophilic drugs | Non-saturable | mM | | Transcortin | 53 | <nM | Corticosteroids | | <nM | ### Acidic (Anion) Drugs * **DRUG - PLASMA PROTEIN:** * Tend to bind exclusively to albumin (e.g. NSAIDs, coumarin anticoagulants). * Saturation of binding to albumin has been reported. ### Basic (Cationic) Drugs * **DRUG - PLASMA PROTEIN:** * Also bind to albumin and lipoproteins. * Especially lipophilic amines (e.g., antidepressants) have a selective affinity for α-1 acid glycoprotein. * Drug - lipoprotein association is relatively weak, modest restrictive influence on drug substrate. ### Acidic (Anion) Drugs * **DRUG - TISSUE PROTEIN:** * Tend to have smaller V (V1<12/kg) due to their high affinity for plasma albumin and low binding affinity for tissue proteins. * Acidic drugs bind well to plasma proteins. ### Basic (Cationic) Drugs * **DRUG - TISSUE PROTEIN:** * Typically have larger V (>12/kg) despite comparable affinity for plasma proteins because of extensive tissue protein binding and other sequestration mechanisms. * **A drug may have great affinity for plasma proteins, BUT still bind to tissue acidic phospholipids.** * **A drug will be located primarily in tissue if the drug has greater affinity to tissue proteins (lipids) than plasma.** This refers to high affinity to tissue & low affinity to albumin.