Pharmacokinetics: The Absorption, Distribution, …

1 27456X123 0 =+789 % TERMS achlorhydria adipose albumin aqueous bioavailability bioequivalent biotransformation blood-brain barrier capillarypermeability cardiac decompen-sation carrier-mediatedtransport catalyze concentrationgradient dissolution distribution epithelium equilibrium excretionChapter 3 Pharmacokinetics: The Absorption, distribution , andExcretion of DrugsOBJECTIVESA fter studying this chapter, the reader should be able to: Explain the meaning of the terms absorption , distribu-tion, metabolism, and excretion. List two physiologic factors that can alter each of theprocesses of absorption , distribution , and excretion. Explain how bioavailability can impact drug responseand product selection. Compare the roles of passive diffusion and carrier-medi-ated transport in drug absorption . Describe two types of drug interaction and explain howthey might affect drug response and safety. 28 Practical Pharmacology for the Pharmacy TechnicianSafe and effective drug treatment is not only a function of the physical and chemical prop-erties of drugs, but also a function of how the human body responds to the administrationof medication.

2 The study of the bodily processes that affect the movement of a drug in thebody is referred to as pharmacokinetics. To understand the pharmacology of drugs, thepharmacy technician must also understand the four fundamental pathways of drug move-ment and modification in the body (Fig. ). First, drug absorption from the site of admin-istration permits entry of the compound into the blood stream. Once absorbed, the drug maythen leave the blood stream and disperse into the tissues and intracellular fluids where itcan reversibly bind to receptors. This dispersal is called distribution . While some drug mol-ecules are binding to receptors, others may be released from the receptors and be picked upagain by the bloodstream. Drug particles in the blood stream are available to undergo bio-chemical changes, referred to as metabolism, in the liver or other tissues. Finally, the drugand its metabolitesare excreted from the body in urine or feces.

3 Metabolism and excretionare both pathways of drug elimination from the , distribution , metabolism, and excretion are sometimes referred to collec-tively as ADME processes. These processes determine when the drug appears in the bloodstream and for how long it remains there. In order for a drug to cause a therapeutic re-sponse, it must reach adequate concentrations in the blood so that it can reach and interactwith drug receptors in adequate numbers to trigger a noticeable action. The course of drugaction is, therefore, directly correlated with the concentration of the drug in the bloodstream, and is dependent upon the ADME processes. extracellular first-pass effect hydrophilic interstitial intracellular lipids metabolism metabolite passive diffusion prodrug saturable process steady state volume of distributionFigure representa-tion of the four fundamen-tal pathways of drug move-ment and modification inthe body, the in bloodsteamDrugin tissuesMetabolitesDistribution Metabolism Metabolism Excretion absorption DrugeliminationdistributionThe process bywhich a drug is carried tosites of action throughoutthe body by the total of allprocesses used by organ-isms to produce and main-tain all cells and systems;also all processes used tohandle consumed sub-stances, whether nutrients,drugs, or product orbyproduct of act or processof excreting.

4 One form ofelimination from the H A P T E R 3 Pharmokinetics: The absorption , distribution , and Excretion of Drugs29 Knowledge of these processes and the ways that they can vary between individuals isan important part of understanding how and why a drug is selected for a patient. To inves-tigate the pharmacokinetic characteristics of a study drug (drug X), researchers will give agroup of healthy adults a standard dose of drug X intravenously (IV) or orally at the startof the study. Blood is drawn from the study subjects repeatedly, at predetermined times,and analyzed for the amount of drug per volume of blood at each point in time. The valueobtained is the serum or plasma concentration of the drug at the time the blood was serum drug concentrations are graphed versus time, the result is the serum concen-tration versus time curve illustrated in Figure is also collected from the study subjects to monitor for the appearance of drug xor related metabolites.

5 Immediately after intravenous administration and at a later time afteroral or other routes of administration, the amount of drug in the blood will reach a peak(peak serum concentration) and then begin to fall off, eventually disappearing from theblood completely. The time it takes for the serum concentration to fall by one half is calledthe t1/2, or half-life, of some point after the drug is no longer detectable in the blood, the last of the drug andits metabolites, which have been filtered out by the kidneys, will also disappear from theurine. Plasma concentration data collected from this type of study is plotted against time andanalyzed in order to understand the behavior of a specific drug in the body. This type of phar-macokinetic data, collected from average adults, is the basis for determining dose, dosing in-tervals, and limitations on the safe use of a drug. However, it is important for the technicianstudent to remember that individuals do not always behave the way the average adult does.

6 Itis individual differences in ADME processes that create the need to modify doses or selectdifferent drugs in order to prevent poor treatment outcomes and adverse is the transfer of a drug from its site of administration to the bloodstream. Therate and extent of absorption depends on the route of administration, the formulation andchemical properties of the drug, and physiologic factors that can impact the site of absorp-Figure concentration versustime curves for oral and IV administrationof a drug. The time it takes for the serumconcentration to fall by one half is calledthe t1/2, or half-life of elimination. Thebioavailability of the drug is determined bycomparing the area under the two , area under curve. (Adapted with per-mission from Harvey RA, Champe PC,Howland RD, et al. Lippincott s IllustratedReviews: Pharmacology, 3rd ed. Baltimore:Lippincott Williams & Wilkins, 2006.)Plasma concentration of drugTimeDrugadministeredAUC (oral)AUC oralBioavailability = x 100 Druggiven orallyDruginjectedAUC(injected)AUC injected30 Practical Pharmacology for the Pharmacy TechnicianFigure gastrointestinaltract is lined with epithelial cells secrete protectivemucus and nutrients and drugspass through simple columnar ep-ithelium.

7 (Reprinted with permis-sion from Cohen BJ, Taylor s Structure and Functionof the Human Body, 8th : Lippincott Williams &Wilkins, 2005, and Cormack Histology, 2nd : Lippincott Williams &Wilkins, 2001.)Lining of tracheaLining of colonCiliaGoblet cellsPseudostratifiedcolumnar epitheliumSimplecolumnarepithelialGoblet cellsABtion. When a drug is administered intravenously, absorption is not required because thedrug is transferred from the administration device directly into the bloodstream. In the caseof intravenous administration, the entire dose of the drug is available to move to the sitesof drug action. Administration by other routes may result in less availability due to incom-plete absorption . When this occurs, less of the drug is delivered by the bloodstream to thesite of action. When a tablet or capsule is swallowed it must dissolve before it can be ab-sorbed. The dissolving of a tablet or capsule is referred to as dissolution.

8 Manufacturingprocesses and the water solubility of the drug affect dissolution rates. Highly water-solublemedications dissolve more readily in the gastrointestinal (GI) tract, while fat-soluble drugsdissolve more slowly. Drugs with smaller particle sizes go into solution more readily. Theinert ingredients added to formulations can also affect their dissolution. Manufacturersmust avoid producing tablets so compacted that they pass through the GI tract without everdissolving. Tablets that dissolve too early are also problematic, because they taste bad andare difficult to swallow. Special formulations or coatings can be used to delay dissolution,thereby protecting the drug from stomach acid or allowing the gradual release of the drugto intentionally lengthen the absorption process. These are referred to as delayed or sus-tained release formulations. Liquid preparations do not require the step of dissolution. Thisexplains the more rapid onset of action seen with liquid formulations as compared with thesame drug given in tablet or capsule dissolution has occurred, the drug molecules must pass through the selectivelypermeable membranes of the cells lining the gastrointestinal tract to reach the on their chemical and physical properties, drugs will be absorbed either by pas-sive diffusion orcarrier-mediated transport across these membranes.

9 Passive diffusion oc-curs when there is a high concentration of the drug on one side of the membrane and a lowconcentration on the other side. This difference from one side of the membrane to the otheris called a concentration is the natural tendency of substances to move from aregion of higher concentration to a region of lower concentration; in other words, sub-stances move down the concentration gradient. Drug molecules move across membranes ormove through pores between the epithelialcells (Fig. ).Diffusion is most efficient withdissolutionProcess of dis-solving or separating intocomponent diffusionTheprocess whereby particlesbecome evenly spread solelyas a result of spontaneousmovement caused by theirrandom thermal transportMovement of a chemicalsubstance, using a carrierprotein and with the expen-diture of energy, against aconcentration gradientAvariation in the concentra-tion of a solute with regardto position; in pharmacol-ogy, especially in relation-ship to a cel-lular tissue that lines inter-nal and external body sur-faces, and is classified intypes according to cellshapes and H A P T E R 3 Pharmokinetics: The absorption , distribution , and Excretion of Drugs31drugs that are small molecules.

10 This movement is solely driven by the kinetic energy withinmolecules, and continues until concentrations reach equilibrium. When equilibrium exists,the concentration of the substance is approximately equal on both sides of the diffusion does not involve a carrier molecule and the process is not a saturableprocess. Saturable processes are limited to a certain rate of activity by some aspect of theprocess. The vast majority of drugs gain access to the blood stream by diffusion. Drugs,which are usually somewhat lipid-soluble (fat-soluble), readily move across most biologi-cal membranes. Those drugs that are highly water-soluble penetrate the cell membranethrough few drugs that closely resemble naturally occurring compounds are absorbed viacarrier-mediated transport. This process requires carrier proteins that attach to and activelycarry the drug molecules across the membrane, utilizing a natural pump mechanism.