Drug distribution

Rate of drug distribution:Depends on:<ul><li>Tissue perfusion</li><li>Permeability of tissue membranes</li><li>Physicochemical properties of the drug</li><li>Binding of drug to plasma proteins - only unbound drug crosses membrane</li><li>Binding to acidic phospholipids in tissue membranes</li></ul> Perfusion limited distribution:<ul><li>When tissue or cell membrane is not barrier for drug distribution meaning perfusion is the limiting factor</li><li>Perfusion differs between tissues</li><li>In highly perfused tissues equilibrium is reached rapidly</li><li>In poorly perfused equilibrium is reached slowly</li></ul><img alt="Blood flow and perfusion rate differ across tissues and these differences affect drug distribution Organ Brain Lungs Liver Kidneys Muscle (inactive) Adipose % of body weight 2.0 1.6 2.3 0.5 43 15 Blood flow (mL/min) 700 5000 1350 1100 750 200 % of cardiac output 14 100 27 22 15 4 Perfusion rate (ml/min per g of tissue) 0.5 10 0.8 4 0.025 0.025 Adapted from Rowland and Tozer, Clinical Pharmacokinetics 2010 " src="https://knowt-user-attachments.s3.amazonaws.com/f050552d-5fc5-4945-8d5f-a324e8704cc1.png" /> Permeability limited distribution:<ul><li>Likely to occur with polar ionised molecules and impermeable membranes (such as blood brain barrier)</li><li>Likely to involve active transport</li></ul> Extent of drug distribution:<ul><li>Defined as apparent volume of distribution (V,Vd)</li><li>based on the equilibrium concept- the distribution equilibrium between the drug in the blood and the drug in the tissue has been achieved</li><li> V = concentration (c) / amount of drug in body at equilibrium (A)</li></ul> Apparent volume of distribution:<ul><li>Vd= amount of drug in body at equilibrium/ drug concentration in plasma </li></ul><img alt="Apparent volume of distribution Value depends on reference fluid used for measurements (plasma, blood, unbound drug) Cb, C and Cu can differ as a consequence of binding of drugs to cells and plasma proteins However, at equilibrium: amount plasma blood u plasma water Cb — concentration of a drug in the blood, C — concentration of a drug in plasma, Cu — unbound plasma concentration of a drug " src="https://knowt-user-attachments.s3.amazonaws.com/ae1f88ee-3d13-483e-86ca-44168e52813d.png" /> What affects the value of volume distribution:<ul><li>Affinity of drug binding to plasma proteins, blood cells and tissue components</li><li>Acidic drugs have string affinity plasma proteins</li><li>Basic drugs have a higher volume of distribution</li><li>Monoclonal antibodies generally low volume distribution</li></ul> Location of drug:<img alt="Location of drug Fraction of drug in body in plasma Plasma volume (Vp) • C V=IOO L 3% of drug in plasma Fraction of drug in body outside of plasma (including blood cells) V - vp = vp/V -1 - vp1V " src="https://knowt-user-attachments.s3.amazonaws.com/fe531f93-fba9-45c2-9fab-d42387fee752.png" /> Clinical relevance of volume of distribution:<ul><li>Important to determine the loading dose of a drug, which is initially a higher dose to achieve target concentration rapidly, followed by a lower maintenance dose</li></ul> Plasma Protein binding:<ul><li>Only the unbound drug diffuses into tissues in order to have pharmacological effect or to be eliminated</li></ul><img alt="Plasma protein binding Representative proteins to which drugs bind in plasma: ALBUMIN

acidic (e.g., warfarin) and neutral drugs (e.g., cyclosporine) • ACID GLYCOPROTEIN -basic drugs • GLOBULINS - steroids Generally a reversible and very rapid process Drug + Protein Drug-Protein complex 55% 1% 45% Plasma SalWMinerals Protei ns Buffy Coat White blood cells Red Blood Cells " src="https://knowt-user-attachments.s3.amazonaws.com/982d70f4-1ac6-4bd8-bf15-8d257dff6a5b.png" /><ul><li>Fu is the fraction of drug unbound in the unbound</li><li>Dependent on the affinity of the protein for the drug and protein and drug concentration.</li><li>1-Fu is the fraction of drug bound</li><li>When Fu is constant, changes in total plasma concentration reflect changes in unbound drug concentration (C= Cu/fu)</li></ul>