As the chief organ of drug biotransfor-mation, the liver is richly supplied withblood, of which 1100 mL is receivedeach minute from the intestinesthrough the portal vein and 350 mLthrough the hepatic artery, comprisingnearly 1/3 of cardiac output. The bloodcontent of hepatic vessels and sinusoidsamounts to 500 mL. Due to the widen-ing of the portal lumen, intrahepaticblood flow decelerates. Moreover,the endothelial lining of hepatic sinu-soids contains pores largeenough to permit rapid exit of plasmaproteins. Thus, blood and hepatic paren-chyma are able to maintain intimatecontact and intensive exchange of sub-stances, which is further facilitated bymicrovilli covering the hepatocyte sur-faces abutting Disse’s spaces.The hepatocyte secretes biliaryfluid into the bile canaliculi (darkgreen), tubular intercellular clefts thatare sealed off from the blood spaces bytight junctions. Secretory activity in thehepatocytes results in movement offluid towards the canalicular space.The hepatocyte has an abundance of en-zymes carrying out metabolic functions.These are localized in part in mitochon-dria, in part on the membranes of therough (rER) or smooth (sER) endoplas-mic reticulum.Enzymes of the sER play a most im-portant role in drug biotransformation.At this site, molecular oxygen is used inoxidative reactions. Because these en-zymes can catalyze either hydroxylationor oxidative cleavage of -N-C- or -O-C-bonds, they are referred to as “mixed-function” oxidases or hydroxylases. Theessential component of this enzymesystem is cytochrome P450, which in itsoxidized state binds drug substrates (R-H). The FeIII-P450-RH binary complex isfirst reduced by NADPH, then forms theternarycomplex,O2-FeII-P450-RH,which accepts a second electron and fi-nally disintegrates into FeIII-P450, oneequivalent of H2O, and hydroxylateddrug (R-OH).
Compared with hydrophilic drugsnot undergoing transport, lipophilicdrugs are more rapidly taken up fromthe blood into hepatocytes and morereadily gain access to mixed-functionoxidases embedded in sER membranes.For instance, a drug having lipophilicityby virtue of an aromatic substituent(phenyl ring) can be hydroxylatedand, thus, become more hydrophilic. Besides oxi-dases, sER also contains reductases andglucuronyl transferases. The latter con-jugate glucuronic acid with hydroxyl,carboxyl, amine, and amide groups; hence, also phenolic products ofphase I metabolism (Phase II conjuga-tion). Phase I and Phase II metabolitescan be transported back into the blood— probably via a gradient-dependentcarrier — or actively secreted into bile.Prolonged exposure to certain sub-strates, such as phenobarbital, carbama-zepine, rifampicin results in a prolifera-tion of sER membranes.This enzyme induction, a load-depen-dent hypertrophy, affects equally all en-zymes localized on sER membranes. En-zyme induction leads to acceleratedbiotransformation, not only of the in-ducing agent but also of other drugs (aform of drug interaction). With contin-ued exposure, induction develops in afew days, resulting in an increase in re-action velocity, maximally 2–3 fold, thatdisappears after removal of the induc-ing agent.
Monday, February 16, 2009
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.
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.
Thursday, January 15, 2009
Blood-Tissue Barriers
Drugs are transported in the blood todifferent tissues of the body. In order toreach their sites of action, they mustleave the bloodstream. Drug permea-tion occurs largely in the capillary bed,where both surface area and time avail-able for exchange are maximal (exten-sive vascular branching, low velocity offlow). The capillary wall forms theblood-tissue barrier. Basically, thisconsists of an endothelial cell layer anda basement membrane enveloping thelatter (solid black line in the schematicdrawings). The endothelial cells are“riveted” to each other by tight junc-tions or occluding zonulae (labelled Z inthe electron micrograph, top left) suchthat no clefts, gaps, or pores remain thatwould permit drugs to pass unimpededfrom the blood into the interstitial fluid.
The blood-tissue barrier is devel-oped differently in the various capillarybeds. Permeability to drugs of the capil-lary wall is determined by the structuraland functional characteristics of the en-dothelial cells. In many capillary beds,e.g., those of cardiac muscle, endothe-lial cells are characterized by pro-nounced endo- and transcytotic activ-ity, as evidenced by numerous invagina-tions and vesicles (arrows in the EM mi-crograph, top right).
Transcytotic activ-ity entails transport of fluid or macro-molecules from the blood into the inter-stitium and vice versa. Any solutestrapped in the fluid, including drugs,may traverse the blood-tissue barrier. Inthis form of transport, the physico-chemical properties of drugs are of littleimportance.In some capillary beds (e.g., in thepancreas), endothelial cells exhibit fen-estrations. Although the cells are tight-ly connected by continuous junctions,they possess pores (arrows in EM mi-crograph, bottom right) that are closedonly by diaphragms. Both the dia-phragm and basement membrane canbe readily penetrated by substances oflow molecular weight — the majority ofdrugs — but less so by macromolecules,e.g., proteins such as insulin (G: insulinstorage granules. Penetrability of mac-romolecules is determined by molecu-lar size and electrical charge.
Fenestrat-ed endothelia are found in the capillar-ies of the gut and endocrine glands.In the central nervous system(brain and spinal cord), capillary endo-thelia lack pores and there is little trans-cytotic activity. In order to cross theblood-brain barrier, drugs must diffusetranscellularly, i.e., penetrate the lumi-nal and basal membrane of endothelialcells. Drug movement along this pathrequires specific physicochemical prop-erties (p. 26) or the presence of a trans-port mechanism (e.g., L-dopa, p. 188).Thus, the blood-brain barrier is perme-able only to certain types of drugs.Drugs exchange freely betweenblood and interstitium in the liver,where endothelial cells exhibit largefenestrations (100 nm in diameter) fac-ing Disse’s spaces (D) and where neitherdiaphragms nor basement membranesimpede drug movement.
Diffusion bar-riers are also present beyond the capil-lary wall: e.g., placental barrier of fusedsyncytiotrophoblast cells; blood: testi-cle barrier — junctions interconnectingSertoli cells; brain choroid plexus: bloodbarrier — occluding junctions betweenependymal cells.
The blood-tissue barrier is devel-oped differently in the various capillarybeds. Permeability to drugs of the capil-lary wall is determined by the structuraland functional characteristics of the en-dothelial cells. In many capillary beds,e.g., those of cardiac muscle, endothe-lial cells are characterized by pro-nounced endo- and transcytotic activ-ity, as evidenced by numerous invagina-tions and vesicles (arrows in the EM mi-crograph, top right).
Transcytotic activ-ity entails transport of fluid or macro-molecules from the blood into the inter-stitium and vice versa. Any solutestrapped in the fluid, including drugs,may traverse the blood-tissue barrier. Inthis form of transport, the physico-chemical properties of drugs are of littleimportance.In some capillary beds (e.g., in thepancreas), endothelial cells exhibit fen-estrations. Although the cells are tight-ly connected by continuous junctions,they possess pores (arrows in EM mi-crograph, bottom right) that are closedonly by diaphragms. Both the dia-phragm and basement membrane canbe readily penetrated by substances oflow molecular weight — the majority ofdrugs — but less so by macromolecules,e.g., proteins such as insulin (G: insulinstorage granules. Penetrability of mac-romolecules is determined by molecu-lar size and electrical charge.
Fenestrat-ed endothelia are found in the capillar-ies of the gut and endocrine glands.In the central nervous system(brain and spinal cord), capillary endo-thelia lack pores and there is little trans-cytotic activity. In order to cross theblood-brain barrier, drugs must diffusetranscellularly, i.e., penetrate the lumi-nal and basal membrane of endothelialcells. Drug movement along this pathrequires specific physicochemical prop-erties (p. 26) or the presence of a trans-port mechanism (e.g., L-dopa, p. 188).Thus, the blood-brain barrier is perme-able only to certain types of drugs.Drugs exchange freely betweenblood and interstitium in the liver,where endothelial cells exhibit largefenestrations (100 nm in diameter) fac-ing Disse’s spaces (D) and where neitherdiaphragms nor basement membranesimpede drug movement.
Diffusion bar-riers are also present beyond the capil-lary wall: e.g., placental barrier of fusedsyncytiotrophoblast cells; blood: testi-cle barrier — junctions interconnectingSertoli cells; brain choroid plexus: bloodbarrier — occluding junctions betweenependymal cells.
External Barriers of the Body
Prior to its uptake into the blood (i.e.,during absorption), a drug has to over-come barriers that demarcate the bodyfrom its surroundings, i.e., separate theinternal milieu from the external mi-lieu. These boundaries are formed bythe skin and mucous membranes.When absorption takes place in thegut (enteral absorption), the intestinalepithelium is the barrier. This single-layered epithelium is made up of ente-rocytes and mucus-producing gobletcells. On their luminal side, these cellsare joined together by zonulae occlu-dentes (indicated by black dots in the in-set, bottom left).
A zonula occludens ortight junction is a region in which thephospholipid membranes of two cellsestablish close contact and becomejoined via integral membrane proteins(semicircular inset, left center). The re-gion of fusion surrounds each cell like aring, so that neighboring cells are weld-ed together in a continuous belt. In thismanner, an unbroken phospholipidlayer is formed (yellow area in the sche-matic drawing, bottom left) and acts asa continuous barrier between the twospaces separated by the cell layer – inthe case of the gut, the intestinal lumen(dark blue) and the interstitial space(light blue).
The efficiency with whichsuch a barrier restricts exchange of sub-stances can be increased by arrangingthese occluding junctions in multiplearrays, as for instance in the endotheli-um of cerebral blood vessels. The con-necting proteins (connexins) further-more serve to restrict mixing of otherfunctional membrane proteins (ionpumps, ion channels) that occupy spe-cific areas of the cell membrane.This phospholipid bilayer repre-sents the intestinal mucosa-blood bar-rier that a drug must cross during its en-teral absorption. Eligible drugs are thosewhose physicochemical properties al-low permeation through the lipophilicmembrane interior (yellow) or that aresubject to a special carrier transportmechanism.
Absorption of such drugs proceeds rapidly, because the absorbingsurface is greatly enlarged due to theformation of the epithelial brush border(submicroscopic foldings of the plasma-lemma). The absorbability of a drug ischaracterized by the absorption quo-tient, that is, the amount absorbed di-vided by the amount in the gut availablefor absorption.In the respiratory tract, cilia-bear-ing epithelial cells are also joined on theluminal side by zonulae occludentes, sothat the bronchial space and the inter-stitium are separated by a continuousphospholipid barrier.With sublingual or buccal applica-tion, a drug encounters the non-kerati-nized, multilayered squamous epitheli-um of the oral mucosa.
Here, the cellsestablish punctate contacts with eachother in the form of desmosomes (notshown); however, these do not seal theintercellular clefts. Instead, the cellshave the property of sequestering phos-pholipid-containing membrane frag-ments that assemble into layers withinthe extracellular space (semicircular in-set, center right). In this manner, a con-tinuous phospholipid barrier arises alsoinside squamous epithelia, although atan extracellular location, unlike that ofintestinal epithelia. A similar barrierprinciple operates in the multilayeredkeratinized squamous epithelium of theouter skin. The presence of a continu-ous phospholipid layer means thatsquamous epithelia will permit passageof lipophilic drugs only, i.e., agents ca-pable of diffusing through phospholipidmembranes, with the epithelial thick-ness determining the extent and speedof absorption. In addition, cutaneous ab-sorption is impeded by the keratinlayer, the stratum corneum, which isvery unevenly developed in various are-as of the skin.
A zonula occludens ortight junction is a region in which thephospholipid membranes of two cellsestablish close contact and becomejoined via integral membrane proteins(semicircular inset, left center). The re-gion of fusion surrounds each cell like aring, so that neighboring cells are weld-ed together in a continuous belt. In thismanner, an unbroken phospholipidlayer is formed (yellow area in the sche-matic drawing, bottom left) and acts asa continuous barrier between the twospaces separated by the cell layer – inthe case of the gut, the intestinal lumen(dark blue) and the interstitial space(light blue).
The efficiency with whichsuch a barrier restricts exchange of sub-stances can be increased by arrangingthese occluding junctions in multiplearrays, as for instance in the endotheli-um of cerebral blood vessels. The con-necting proteins (connexins) further-more serve to restrict mixing of otherfunctional membrane proteins (ionpumps, ion channels) that occupy spe-cific areas of the cell membrane.This phospholipid bilayer repre-sents the intestinal mucosa-blood bar-rier that a drug must cross during its en-teral absorption. Eligible drugs are thosewhose physicochemical properties al-low permeation through the lipophilicmembrane interior (yellow) or that aresubject to a special carrier transportmechanism.
Absorption of such drugs proceeds rapidly, because the absorbingsurface is greatly enlarged due to theformation of the epithelial brush border(submicroscopic foldings of the plasma-lemma). The absorbability of a drug ischaracterized by the absorption quo-tient, that is, the amount absorbed di-vided by the amount in the gut availablefor absorption.In the respiratory tract, cilia-bear-ing epithelial cells are also joined on theluminal side by zonulae occludentes, sothat the bronchial space and the inter-stitium are separated by a continuousphospholipid barrier.With sublingual or buccal applica-tion, a drug encounters the non-kerati-nized, multilayered squamous epitheli-um of the oral mucosa.
Here, the cellsestablish punctate contacts with eachother in the form of desmosomes (notshown); however, these do not seal theintercellular clefts. Instead, the cellshave the property of sequestering phos-pholipid-containing membrane frag-ments that assemble into layers withinthe extracellular space (semicircular in-set, center right). In this manner, a con-tinuous phospholipid barrier arises alsoinside squamous epithelia, although atan extracellular location, unlike that ofintestinal epithelia. A similar barrierprinciple operates in the multilayeredkeratinized squamous epithelium of theouter skin. The presence of a continu-ous phospholipid layer means thatsquamous epithelia will permit passageof lipophilic drugs only, i.e., agents ca-pable of diffusing through phospholipidmembranes, with the epithelial thick-ness determining the extent and speedof absorption. In addition, cutaneous ab-sorption is impeded by the keratinlayer, the stratum corneum, which isvery unevenly developed in various are-as of the skin.
Potential Targets of Drug Action
Drugs are designed to exert a selectiveinfluence on vital processes in order toalleviate or eliminate symptoms of dis-ease. The smallest basic unit of an or-ganism is the cell. The outer cell mem-brane, or plasmalemma, effectively de-marcates the cell from its surroundings,thus permitting a large degree of inter-nal autonomy. Embedded in the plas-malemma are transport proteins thatserve to mediate controlled metabolicexchange with the cellular environment.
Theseincludeenergy-consumingpumps (e.g., Na, K-ATPase, p. 130), car-riers (e.g., for Na/glucose-cotransport, p.178), and ion channels e.g., for sodium(p. 136) or calcium (p. 122)
(1).Functional coordination betweensingle cells is a prerequisite for viabilityof the organism, hence also for the sur-vival of individual cells. Cell functionsare regulated by means of messengersubstances for the transfer of informa-tion. Included among these are “trans-mitters” released from nerves, whichthe cell is able to recognize with thehelp of specialized membrane bindingsites or receptors. Hormones secretedby endocrine glands into the blood, theninto the extracellular fluid, representanother class of chemical signals. Final-ly, signalling substances can originatefrom neighboring cells, e.g., prostaglan-dins (p. 196) and cytokines.The effect of a drug frequently re-sults from interference with cellularfunction. Receptors for the recognitionof endogenous transmitters are obvioussites of drug action (receptor agonistsand antagonists, p. 60). Altered activityof transport systems affects cell func-tion (e.g., cardiac glycosides, p. 130;loop diuretics, p. 162; calcium-antago-nists, p. 122). Drugs may also directlyinterfere with intracellular metabolicprocesses, for instance by inhibiting(phosphodiesterase inhibitors, p. 132)or activating (organic nitrates, p. 120)an enzyme.
(2).In contrast to drugs acting from theoutside on cell membrane constituents, agents acting in the cell’s interior needto penetrate the cell membrane.The cell membrane basically con-sists of a phospholipid bilayer (80Å =8 nm in thickness) in which are embed-ded proteins (integral membrane pro-teins, such as receptors and transportmolecules). Phospholipid moleculescontain two long-chain fatty acids in es-ter linkage with two of the three hy-droxyl groups of glycerol. Bound to thethird hydroxyl group is phosphoric acid,which, in turn, carries a further residue,e.g., choline, (phosphatidylcholine = lec-ithin), the amino acid serine (phosphat-idylserine) or the cyclic polyhydric alco-hol inositol (phosphatidylinositol). Interms of solubility, phospholipids areamphiphilic: the tail region containingthe apolar fatty acid chains is lipophilic,the remainder – the polar head – is hy-drophilic. By virtue of these properties,phospholipids aggregate spontaneouslyinto a bilayer in an aqueous medium,their polar heads directed outwards intothe aqueous medium, the fatty acidchains facing each other and projectinginto the inside of the membrane.
(3).The hydrophobic interior of thephospholipid membrane constitutes adiffusion barrier virtually imperme-able for charged particles. Apolar parti-cles, however, penetrate the membraneeasily. This is of major importance withrespect to the absorption, distribution,and elimination of drugs.
Theseincludeenergy-consumingpumps (e.g., Na, K-ATPase, p. 130), car-riers (e.g., for Na/glucose-cotransport, p.178), and ion channels e.g., for sodium(p. 136) or calcium (p. 122)
(1).Functional coordination betweensingle cells is a prerequisite for viabilityof the organism, hence also for the sur-vival of individual cells. Cell functionsare regulated by means of messengersubstances for the transfer of informa-tion. Included among these are “trans-mitters” released from nerves, whichthe cell is able to recognize with thehelp of specialized membrane bindingsites or receptors. Hormones secretedby endocrine glands into the blood, theninto the extracellular fluid, representanother class of chemical signals. Final-ly, signalling substances can originatefrom neighboring cells, e.g., prostaglan-dins (p. 196) and cytokines.The effect of a drug frequently re-sults from interference with cellularfunction. Receptors for the recognitionof endogenous transmitters are obvioussites of drug action (receptor agonistsand antagonists, p. 60). Altered activityof transport systems affects cell func-tion (e.g., cardiac glycosides, p. 130;loop diuretics, p. 162; calcium-antago-nists, p. 122). Drugs may also directlyinterfere with intracellular metabolicprocesses, for instance by inhibiting(phosphodiesterase inhibitors, p. 132)or activating (organic nitrates, p. 120)an enzyme.
(2).In contrast to drugs acting from theoutside on cell membrane constituents, agents acting in the cell’s interior needto penetrate the cell membrane.The cell membrane basically con-sists of a phospholipid bilayer (80Å =8 nm in thickness) in which are embed-ded proteins (integral membrane pro-teins, such as receptors and transportmolecules). Phospholipid moleculescontain two long-chain fatty acids in es-ter linkage with two of the three hy-droxyl groups of glycerol. Bound to thethird hydroxyl group is phosphoric acid,which, in turn, carries a further residue,e.g., choline, (phosphatidylcholine = lec-ithin), the amino acid serine (phosphat-idylserine) or the cyclic polyhydric alco-hol inositol (phosphatidylinositol). Interms of solubility, phospholipids areamphiphilic: the tail region containingthe apolar fatty acid chains is lipophilic,the remainder – the polar head – is hy-drophilic. By virtue of these properties,phospholipids aggregate spontaneouslyinto a bilayer in an aqueous medium,their polar heads directed outwards intothe aqueous medium, the fatty acidchains facing each other and projectinginto the inside of the membrane.
(3).The hydrophobic interior of thephospholipid membrane constitutes adiffusion barrier virtually imperme-able for charged particles. Apolar parti-cles, however, penetrate the membraneeasily. This is of major importance withrespect to the absorption, distribution,and elimination of drugs.
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