1Thomas M. Guenthner, Ph.D.Department of PharmacologyUIC College of MedicineE-418 MSB; [email protected] OF DRUG DISPOSITION: ABSORPTION, DISTRIBUTION, AND METABOLISMAbsorptionA. 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 electrochemicalgradient; iv) selective carrier-mediated.# Pinocytosis: Drugs of large molecular weight (MW > 900) may enter cells by pinocytosis orendocytosis.# Passive Diffusion: This is the MOST COMMON mechanism for drug transport. Lipid-soluble drugspermeate across the cell membrane by passive diffusion between the lipid molecules of the cellmembrane.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 hasvilli, the small intestines have microvilli. Therefore, the intestines have a much greater surface areathan the stomach. Most drugs can be absorbed by the intestines. Generally speaking the presenceof 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)/LD - Diffusion Coefficient (Molecular Property of Drug)# Oil/Water partition coefficient (Kp) of the drug.# Molecular size of the drug.2( )( )pH - pK = logUNPROTONATED FORM RPROTONATED FORM RHaK =CCpoilwaterWhere Coil is the concentration of drug in the oil or organic phase, and Cwater is the concentration of thedrug in the water or aqueous phase# The extent of ionization (the pH of the environment and the pKa of the drug). # Gastric absorption: The pH of gastric juice is low (1 to 3). Weak bases will be ionized and will bepoorly 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 thegastric juice where they become ionized and trapped. They may be absorbed later when they reachthe intestines.# Intestinal absorption: The pH of intestinal juice is more basic than gastric juice (5 to 6). Here mostweak bases will be unionized and will be readily absorbed. In contrast, most weak acids will beionized and will be poorly absorbed.34CC=1 + 101 + 1012(pH -pK )(pH - pK )1 a2 aCC=1 + 101 + 1012(pK - pH )(pK - pH )a 1a 2FORMULAS FOR CALCULATING THE RATIO OF DRUG CONCENTRATIONSIN TWO SEPARATE COMPARTMENTSFOR AN ACID:FOR A BASE:Effect of pH on Gastric AbsorptionDrug pKa% Absorbed in 1 hour (pH = 1) % Absorbed in 1 hour (pH = 8)Acids5-sulfosalicylic acid < 1 0 0salicylic acid 3.0 61 13thiopental 7.6 46 34basesaniline 4.6 6 56quinine 8.4 0 18Effect of Partition Coefficient on Drug AbsorptionBarbiturateBarbitalSecobarbitalThiopentalpKa7.87.97.6Kp (Hept/H2O)0.0010.13.3% Absorbed in 1 hour430465# 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. Cm ax p r edi c ts t he deg r e e o f p h arm ac olog i cal (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 ingredi-ents included in the preparation, and the crystalline properties and rates of dissolution of the drug itself.6III. Distribution.Factors That Affect the Rate of Drug Distribution# Lipid solubility (Kp) # Degree of ionization # Molecular weight # Blood flowFactors That Affect the Extent of Drug Distribution# Lipid solubility (Kp) # Plasma protein binding # Tissue bindingCapillary Barriers to Drugs:# Capillaries with maculae ("spot junctions"). # Fenestrated capillaries (kidney).# Capillaries with occluding zonulae (Blood-Brain Barrier)7Transport of Drugs Across the PlacentaMaternal-Fetal Equilibration of Tubocurarine and ThiopentalTime (min) Maternal TubocurarineFetalTubocurarineMaternalThiopentalFetalThiopental5 3 0 8.5 5.56 3.2 0 8 3.59 1.1 0.1 4.8 2.512 2.1 0.1 3 2Drug 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, glycineconjugationNet Result (Usually): Alteration of pharmacological activity (potentiation or deactivation), facilitation ofexcretion.A. Phase I reactions1) The Cytochrome P450 Monooxygenases (CYP)The active site of cytochrome
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