Thomas M Guenthner Ph D Department of Pharmacology UIC College of Medicine E 418 MSB 996 2558 tmg uic edu PRINCIPLES OF DRUG DISPOSITION ABSORPTION DISTRIBUTION AND METABOLISM Absorption A Definition Movement of a drug from its site of administration to the systemic arterial circulation B Movement of Drugs Across Membranes Active Transport i energy dependent ii saturable iii against an electrochemical gradient iv selective carrier mediated Facilitated Diffusion i requires NO energy ii saturable iii NEVER against an electrochemical gradient iv selective carrier mediated Pinocytosis Drugs of large molecular weight MW 900 may enter cells by pinocytosis or endocytosis Passive Diffusion This is the MOST COMMON mechanism for drug transport Lipid soluble drugs permeate across the cell membrane by passive diffusion between the lipid molecules of the cell membrane C Absorption of Drugs by the Gastrointestinal Tract Epithelial Barriers to Drugs Epithelial cells in the GI are joined to one another by occluding zonulae tight junctions Drugs must pass THROUGH the cells and can not pass around the cells Surface Area Larger surface areas absorb drugs faster than smaller ones The gastric mucosa has villi the small intestines have microvilli Therefore the intestines have a much greater surface area than the stomach Most drugs can be absorbed by the intestines Generally speaking the presence of food will slow gastric emptying time and will slow the absorption of an orally administered drug Also many drugs slow gastric emptying and may slow the absorption of a second drug D Chemical Factors That Affect non ionic passive diffusion Solubility in water Concentration of the drug Fick s Law Rate of Passive Diffusion J D A C1 C2 L D Diffusion Coefficient Molecular Property of Drug Oil Water partition coefficient Kp of the drug Molecular size of the drug 1 Kp Coil Cwater Where Coil is the concentration of drug in the oil or organic phase and Cwater is the concentration of the drug in the water or aqueous phase The extent of ionization the pH of the environment and the pKa of the drug pH pKa log UNPROTONATED FORM R PROTONATED FORM RH Gastric absorption The pH of gastric juice is low 1 to 3 Weak bases will be ionized and will be poorly absorbed Weak acids will be unionized and will be absorbed well Furthermore weak bases even if they are administered IV may cross the capillaries and the gastric mucosa and enter the gastric juice where they become ionized and trapped They may be absorbed later when they reach the intestines Intestinal absorption The pH of intestinal juice is more basic than gastric juice 5 to 6 Here most weak bases will be unionized and will be readily absorbed In contrast most weak acids will be ionized and will be poorly absorbed 2 3 FORMULAS FOR CALCULATING THE RATIO OF DRUG CONCENTRATIONS IN TWO SEPARATE COMPARTMENTS FOR AN ACID FOR A BASE C1 1 10 pKa pH1 C2 1 10 pKa pH2 C1 1 10 pH1 pKa C2 1 10 pH2 pKa Effect of pH on Gastric Absorption Drug pKa Absorbed in 1 hour pH 1 Absorbed in 1 hour pH 8 5 sulfosalicylic acid 1 0 0 salicylic acid 3 0 61 13 thiopental 7 6 46 34 aniline 4 6 6 56 quinine 8 4 0 18 Acids bases Effect of Partition Coefficient on Drug Absorption Barbiturate Barbital Secobarbital Thiopental pKa 7 8 7 9 7 6 Kp Hept H2O 0 001 0 1 3 3 4 Absorbed in 1 hour 4 30 46 Bioavailability The Bioavailable Fraction usually written F is the percentile fraction of the total dose that enters the systemic circulation With the IV route of administration 100 of the drug enters the systemic circulation and F is equal to 1 With the oral route only a fraction of the total dose enters the systemic circulation and the Bioavailable Fraction F is equal to that fraction One can compare the Bioavailable Fractions of two preparations or of a single preparation under different conditions by comparing the areas under the curve of plots of plasma drug concentration versus time F is not the only important parameter of bioavailability maximal plasma levels or concentrations Cmax can also vary for different pharmaceutical preparations Cmax predicts the degree of pharmacological or toxicological effect Two separate pharmaceutical preparations may contain the same amount of the same compound but they may not exhibit identical bioavailability and may not yield identical plasma drug concentrations in the same patient The cardiac drug digoxin serves as a classic example The figure below illustrates the serum digoxin levels obtained in four different patients S S H R C H and M B after oral administration of four different digoxin preparations A B1 B2 and C each containing the same amount of drug Each preparation produces distinct plasma levels and the areas under the concentration time curves are different each preparation has a different bioavailability Factors that can affect bioavailability include the size and type of the pill capsule the type of inert ingredients included in the preparation and the crystalline properties and rates of dissolution of the drug itself 5 III Distribution Factors That Affect the Rate of Drug Distribution Lipid solubility Kp Degree of ionization Molecular weight Blood flow Factors That Affect the Extent of Drug Distribution Lipid solubility Kp Plasma protein binding Tissue binding Capillary Barriers to Drugs Capillaries with maculae spot junctions Fenestrated capillaries kidney Capillaries with occluding zonulae Blood Brain Barrier 6 Transport of Drugs Across the Placenta Maternal Fetal Equilibration of Tubocurarine and Thiopental Time min Maternal Tubocurarine Fetal Tubocurarine Maternal Thiopental Fetal Thiopental 5 3 0 8 5 5 5 6 3 2 0 8 3 5 9 1 1 0 1 4 8 2 5 12 2 1 0 1 3 2 Drug Metabolism Phase I reactions a change in the chemical structure of the drug molecule oxidation reduction oxygenation dealkylation hydrolysis Phase II reactions combination conjugation of the drug molecule with a second endogenous substance glucuronidation sulfation mercapturic acid formation glutathione acetylation methylation glycine conjugation Net Result Usually Alteration of pharmacological activity potentiation or deactivation facilitation of excretion A Phase I reactions 1 The Cytochrome P450 Monooxygenases CYP The active site of cytochrome P 450 Steps of the reaction Drug substrate binds to P450 P 450 drug complex is reduced by NADPH Molecular oxygen O2 binds to reduced P 450 drug complex Oxygen is reduced to an activated state One atom of oxygen combines with the drug substrate the other atom
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