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Dr. Phil Rowe Reader in Pharmaceutical Computing School of Pharmacy & Chemistry John Moores University Liverpool Pharmacokinetics lecture 1 Contents ... • What is ‘Pharmacokinetics’ • Absorption • Distribution Pharmacokinetics “Drug movement” (Greek) The movement of drugs: Into Around Back out of the body ADME Absorption Distribution Metabolism Excretion Elimination Absorption Three mechanisms by which drugs may cross membranes: Passive diffusion Facilitated diffusion Active transport Passive diffusion MUCH more common than any of the others. Passive diffusion Water DRUG Lipid Water Requirements for passive diffusion Water solubility Lipid solubility * Almost all drugs are sufficiently water soluble to undergo passive diffusion, but some do lack the necessary lipid solubility. * In practice, passive diffusion depends mainly on lipid solubility. Efficiency of passive diffusion Efficient Inefficient Hydrocarbons Anaesthetics Alcohols Lipids Most drugs Carbohydrates Proteins Ionised molecules Facilitated diffusion Water Lipid Water DRUG Selective gateway allows entry of one group of molecules, but excludes all others. Active transport Water Lipid Water DRUG Structurally selective. Energy requiring Can operate against the concentration gradient Specificity Passive diffusion Non-specific. Anything lipid soluble Facilitated diffusion Active transport Structurally specific groups of chemicals that fit a carrier molecule Specificity Few drugs handled by facilitated or active transport A molecule can only be handled by facilitated or active transport if the body contains a suitable carrier, so it is not surprising that very few drugs use such mechanisms. There are some examples. e.g. L-DOPA and gabapentin are transported into the brain by the Large neutral Amino Acid Transporter (LAT1) P-glycoproteins (Glycoproteins = proteins with carbohydrates attached) P-gp in the apical cell membrane (facing the gut contents). Substances are absorbed, but then actively pumped back into the gut contents (Efflux). ATP dependent. Gut contents Apical surface Intestinal epithelial cell Basolateral surface Location of P-glycoproteins Organ Intestine Liver Kidney Brain Function Prevent absorption Excretion into bile Excretion into urine Prevent entry from blood into brain Generally a defensive mechanism against foreign substances Examples of substances where intestinal absorption is opposed by P-gp mediated efflux Celiprolol Cyclosporin Dexamethasone Ivermectin Verapamil Vincristine Beta blocker Immunosuppressant Glucocorticoid Anthelmintic Antihypertensive Cytotoxic Wide range of drug groups and chemical structures Induction and inhibition of P-gp Induction Example - Rifampicin increase the amount of P-gp in the intestinal epithelium. Reduces absorption of other substances. Inhibition Example - Large enough dose of verapamil will saturate the P-gp. Other substances then absorbed more easily. Has been suggested as a means to increase absorption of problem molecules. Distribution Kidneys Fat Blood Liver Etc. Factors influencing distribution of a drug: Ability to undergo passive diffusion (Already described) Binding to macromolecules Ion trapping P-glycoproteins (Already described) Plasma protein binding Blood Cell Drug Drug Drug.Protein Lipid Total drug conc in blood greater than in cell. Intra-cellular binding Blood Cell Drug Drug Lipid Drug.Protein Lipid Nucleic acid Total drug conc in blood lower than in cell. Overall binding Blood Cell Drug Drug Drug.Protein Lipid Drug.Protein Lipid Nucleic acid Balance depends upon relative binding affinity in blood and tissues. Ion trapping Stomach (Acid) Blood (Neutral) R-NH2 R-NH2 + R-NH3 + R-NH3 Lipid Basic drugs accumulate in acidic environments. (Acidic drugs accumulate in basic environments.) Terms with which you should be familiar ... Pharmacokinetics Absorption Distribution Metabolism Excretion Elimination ADME Passive diffusion Faciliated diffusion Active transport P-glycoproteins Ion trapping What you should be able to do Distinguish between metabolism and excretion Describe the characteristics of passive diffusion, facilitated diffusion and active transport Predict whether a given molecule will easily undergo passive diffusion Describe the function of P-glycoproteins Identify the factors that may influence the distribution of a given drug
