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<strong>Pharmacokinetics</strong>Distribution: Compartments and Volume of DistributionBloodTissueDrugDrugDrug.ProteinLipidDrug.ProteinNucleic acidLipidFig 3.8 Drug distribution between blood and tissue in the presence of binding to macromolecules in both blood and tissuesBinding to macromolecules may hold drug in either blood or the tissues.3.4.3 P-glycoproteinsIn Chapter 2, we saw how P-glycoproteins in the gut can actively pump drugs across membranes and hence inhibit drugabsorption. P-glyoproteins are also present in other parts of the body and have an effect upon drug distribution betweenblood and tissues.P-glycoproteins seem to have evolved as a mechanism to protect the body from toxic molecules that may be ingested. Thecentral nervous system (CNS) is particularly sensitive to poisoning and one line of defence consists of P-glycoproteins atthe blood brain barrier, which prevent the entry of toxins (and certain drugs) into the CNS.3.4.4 Ion trappingIon trapping arises when an ionisable drug encounters a pH gradient. An example is shown in Figure 3.9.Stomach(Acidic)Blood/Tissues(Neutral)R-NH 2R-NH 2R-NH 3+LipidR-NH 3+Figure 3.9 Ion trapping of a basic drug in the acidic medium of the stomach30Download free ebooks at bookboon.com
<strong>Pharmacokinetics</strong>Distribution: Compartments and Volume of DistributionThe example in Figure 3.9, assumes that a basic drug contains an ionisable nitrogen atom. The stomach contents arestrongly acidic, while blood and tissues are approximately neutral. In its non-ionized form the drug is lipid soluble andable to cross membranes by passive diffusion. However, once ionized it is much more polar and unable to cross.A sequence of events arises:--The highly acidic environment within the stomach, causes an extensive shift in the equilibrium betweenionized and non-ionized drug towards ionization (Hence the dominant arrow in the appropriate direction).--The process described above, reduces the concentration of non-ionized drug in the stomach and createsa disequilibrium, with a lower concentration of non-ionized material in the stomach than in the blood.Consequently, non-ionized drug moves into the stomach contents. (See dominant arrow going from blood tostomach.)--This physical movement depletes the concentration of non-ionized drug in the blood, causing adisequilibrium between ionized and non-ionized drug. This is resolved by re-equilibration - the conversionof ionized into non-ionized drug within the blood. (See final dominant arrow.)By following the heavy arrows, it can be seen that the overall effect is to transfer drug from the blood into the stomachcontents. A practical example of ion trapping is that morphine (an alkaloid) will be found in raised concentrations instomach contents during an autopsy following overdose.The opposite effect would be seen with an acidic drug; at equilibrium there would be higher concentrations of drug inthe blood than in the stomach. The general rule is a kind of ‘attraction of opposites’; acidic drugs accumulate in basicenvironments and basic drugs in acidic ones.Attraction of opposites: Ion trapping will cause an accumulation of basic drugs in any relatively acidic environmentand vice versa.3.5 Volume of distributionThe four factors discussed above will jointly govern the extent to which drug moves out of blood into tissues. Figure 3.10summarizes the spectrum of possibilities. The figure represents drug concentration by the degree of shading. In (a), nearlyall the drug is retained in the blood with very little moving out into the tissues. In (c), we see the opposite pattern, mostof the drug having moved into the tissues. Part (b) represents a more balanced outcome.The ‘Volume of distribution’ is the parameter used to describe the behaviour of a particular drug. A situation such as(a) is conveyed by a small volume of distribution and that in (c) by a large value. The volume of distribution is usuallyrepresented by the symbol ‘V’.31Download free ebooks at bookboon.com
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