Possible Modes of Drug Distribution

Following its uptake into the body, thedrug is distributed in the blood andthrough it to the various tissues of thebody. Distribution may be restricted tothe extracellular space (plasma volumeplus interstitial space) or may alsoextend into the intracellular space.Certain drugs may bind strongly to tis-sue structures, so that plasma concen-trations fall significantly even beforeelimination has begun.After being distributed in blood,macromolecular substances remainlargely confined to the vascular space,because their permeation through theblood-tissue barrier, or endothelium, isimpeded, even where capillaries arefenestrated. This property is exploitedtherapeutically when loss of blood ne-cessitates refilling of the vascular bed,e.g., by infusion of dextran solutions. The vascular space is, moreover,predominantly occupied by substancesbound with high affinity to plasma pro-teins; determination of the plas-ma volume with protein-bound dyes).Unbound, free drug may leave thebloodstream, albeit with varying ease,because the blood-tissue barrier is differently developed in different seg-ments of the vascular tree. These re-gional differences are not illustrated inthe accompanying figures.Distribution in the body is deter-mined by the ability to penetrate mem-branous barriers. Hydrophilicsubstances (e.g., inulin) are neither tak-en up into cells nor bound to cell surfacestructures and can, thus, be used to de-termine the extracellular fluid volume. Some lipophilic substances diffusethrough the cell membrane and, as a re-sult, achieve a uniform distribution.Body weight may be broken downas follows:

Further subdivisions are shown inthe table.The volume ratio interstitial: intra-cellular water varies with age and bodyweight. On a percentage basis, intersti-tial fluid volume is large in premature ornormal neonates (up to 50 % of bodywater), and smaller in the obese and theaged.The concentration of a solutioncorresponds to the amount of sub-stance dissolved in a volume; thus, c= D/V. If the dose of drug and itsplasma concentrationare known, avolume of distributioncan be calcu-lated from V = D/c. However, this repre-sents an apparent volume of distribu-tion (Vapp), because an even distributionin the body is assumed in its calculation.Homogeneous distribution will not oc-cur if drugs are bound to cell mem-branes or to membranes of intracel-lular organelles or are stored withinthe latter. In these cases, Vapp can ex-ceed the actual size of the available fluidvolume. The significance of Vapp as apharmacokinetic parameter is dis-cussed.

Having entered the blood, drugs maybind to the protein molecules that arepresent in abundance, resulting in theformation of drug-protein complexes.Protein binding involves primarily al-bumin and, to a lesser extent, lins and acidic glycoproteins. Otherplasma proteins (e.g., transcortin, trans-ferrin, thyroxin-binding globulin) servespecialized functions in connectionwith specific substances. The degree ofbinding is governed by the concentra-tion of the reactants and the affinity of adrug for a given protein. Albumin con-centration in plasma amounts to4.6 g/100 mL or O.6 mM, and thus pro-vides a very high binding capacity (twosites per molecule). As a rule, drugs ex-hibit much lower affinity (KD approx.10–5 –10–3 M) for plasma proteins thanfor their specific binding sites (recep-tors). In the range of therapeutically rel-evant concentrations, protein binding ofmost drugs increases linearly with con-centration (exceptions: salicylate andcertain sulfonamides).The albumin molecule has differentbinding sites for anionic and cationic li-gands, but van der Waals’ forces alsocontribute. The extent of bindingcorrelates with drug hydrophobicity(repulsion of drug by water).Binding to plasma proteins is in-stantaneous and reversible, i.e., anychange in the concentration of unbounddrug is immediately followed by a cor-responding change in the concentrationof bound drug. Protein binding is ofgreat importance, because it is the con-centration of free drug that determinesthe intensity of the effect. At an identi-cal total plasma concentration (say, 100ng/mL) the effective concentration willbe 90 ng/mL for a drug 10 % bound toprotein, but 1 ng/mL for a drug 99 %bound to protein. The reduction in con-centration of free drug resulting fromprotein binding affects not only the in-tensity of the effect but also biotransfor-mation (e.g., in the liver) and elimina-tion in the kidney, because only free drug will enter hepatic sites of metab-olism or undergo glomerular filtration.When concentrations of free drug fall,drug is resupplied from binding sites onplasma proteins. Binding to plasma pro-tein is equivalent to a depot in prolong-ing the duration of the effect by retard-ing elimination, whereas the intensityof the effect is reduced. If two substanc-es have affinity for the same binding siteon the albumin molecule, they maycompete for that site. One drug may dis-place another from its binding site andthereby elevate the free (effective) con-centration of the displaced drug (a formof drug interaction). Elevation of thefree concentration of the displaced drugmeans increased effectiveness and ac-celerated elimination.A decrease in the concentration ofalbumin (liver disease, nephrotic syn-drome, poor general condition) leads toaltered pharmacokinetics of drugs thatare highly bound to albumin.Plasma protein-bound drugs thatare substrates for transport carriers canbe cleared from blood at great velocity,e.g., p-aminohippurate by the renal tu-bule and sulfobromophthalein by theliver. Clearance rates of these substanc-es can be used to determine renal or he-patic blood flow.