《药理学》课程教学资源（参考书籍）英文版《Color atlas of pharmacology》第二版

28 Distribution in the body nid substance and structurally bound water llowing its uptake into the body. the through it to the various tissues of the the extracellular space(plasma us interstitial extend into the intracellular space(3) Certain drugs may bind strongly to tis- e structures, so that plasma concen- trations fall significantly even befo extracellular elimination has begun(4). Potential aqueous solvent confined to the vascular spac spaces for drug their permeation through the blood-tissue barrier, or endothelium, is mpeded, even where capillaries are Further subdivisions are shown in enestrated. This property is exploited the table. therapeutically when loss of blood ne- cessitates refilling of the vascular bed. cellular water varies with age and body g. by infusion of dextran solutions (p. weight On a percentage basis, intersti- 2). The vascular spac ubstances normal neonates (up to 50% of bod ound with high affinity to plasma pro- water), and smaller in the obese and the teins(p. 30: determination of the plas- aged ma volume with protein-bound dyes). The concentration (c)of a solution Unbound, free drug may leave the corresponds to the amount(D)of sub- because the blood-tissue barrier (p. 24)- D/V. If the dose of drug(D)and its is differently developed in different seg- plasma concentration (c)are known,a ments of the vascular tree. These re. volume of distribution(v)can be calcu- gional differences are not illustrated in lated from V= D/c However, this repre- nts an apparent volume of distrib he body is deter ecause an even distribution mined by the ability to penetrate mem- in the body is assumed in its calculation mogeneous distribution will not oo substances(e. g inulin) are neither tak en up into cells nor bound to cell surface structures and can, thus, be used to de- lular organelles(6)or are stored within nrough the cell membrane a lume. The significance of vapp as a It, achieve a uniform distrib harmacokinetic parameter is dis- dy weight may be bro cussed on p. 44. LOmann, Color Atlas of Pharmacology '2000 Thieme All rights reserved Usage subject to terms and conditions of license

Possible Modes of Drug Distribution Following its uptake into the body, the drug is distributed in the blood (1) and through it to the various tissues of the body. Distribution may be restricted to the extracellular space (plasma volume plus interstitial space) (2) or may also extend into the intracellular space (3). Certain drugs may bind strongly to tis￾sue structures, so that plasma concen￾trations fall significantly even before elimination has begun (4). After being distributed in blood, macromolecular substances remain largely confined to the vascular space, because their permeation through the blood-tissue barrier, or endothelium, is impeded, even where capillaries are fenestrated. This property is exploited therapeutically when loss of blood ne￾cessitates refilling of the vascular bed, e.g., by infusion of dextran solutions (p. 152). The vascular space is, moreover, predominantly occupied by substances bound with high affinity to plasma pro￾teins (p. 30; determination of the plas￾ma volume with protein-bound dyes). Unbound, free drug may leave the bloodstream, albeit with varying ease, because the blood-tissue barrier (p. 24) is differently developed in different seg￾ments of the vascular tree. These re￾gional differences are not illustrated in the accompanying figures. Distribution in the body is deter￾mined by the ability to penetrate mem￾branous barriers (p. 20). Hydrophilic substances (e.g., inulin) are neither tak￾en up into cells nor bound to cell surface structures and can, thus, be used to de￾termine the extracellular fluid volume (2). Some lipophilic substances diffuse through the cell membrane and, as a re￾sult, achieve a uniform distribution (3). Body weight may be broken down as follows: Further subdivisions are shown in the table. The volume ratio interstitial: intra￾cellular water varies with age and body weight. On a percentage basis, intersti￾tial fluid volume is large in premature or normal neonates (up to 50 % of body water), and smaller in the obese and the aged. The concentration (c) of a solution corresponds to the amount (D) of sub￾stance dissolved in a volume (V); thus, c = D/V. If the dose of drug (D) and its plasma concentration (c) are known, a volume of distribution (V) can be calcu￾lated from V = D/c. However, this repre￾sents an apparent volume of distribu￾tion (Vapp), because an even distribution in the body is assumed in its calculation. Homogeneous distribution will not oc￾cur if drugs are bound to cell mem￾branes (5) or to membranes of intracel￾lular organelles (6) or are stored within the latter (7). In these cases, Vapp can ex￾ceed the actual size of the available fluid volume. The significance of Vapp as a pharmacokinetic parameter is dis￾cussed on p. 44.
                     Solid substance and structurally bound water 28 Distribution in the Body intracellular extracellular water water Potential aqueous solvent spaces for drugs Lüllmann, Color Atlas of Pharmacology ' 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

Distribution in the Body 29 istribution in tissue Plasma Aqueous spaces of the org 8 lYsosomes chondria Nucleus A. Compartments for drug distribution LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license

Distribution in the Body 29 A. Compartments for drug distribution Distribution in tissue Aqueous spaces of the organism Plasma Interstitium Erythrocytes Intracellular space 6% 4% 25% 65% Lysosomes Mito￾chondria Cell membrane Nucleus 12 4 3 56 7 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license

30 Distribution in the body Binding to Plasma Proteins drug will enter hepatic sites of metab. lism or undergo glomerular filtration Having entered the blood drugs When concentrations of free drug fall tein is equivale Binding to plasma pro- resent in abundance, resulting in the plasma protei Protein binding involves primarily al- ing the duration of the effect by retard- nation, whereas the intensity ns and acidic glycoproteins. Other the effect is reduced. If two substanc plasma proteins(e.g, transcortin, trans- ferrin, thyroxin-binding globulin)serve he albumin molecule, they may ecialized functions onnection with specific substances. The degree of ce another from its binding site and binding is governed by the concentra- thereby elevate the free(effective)con- drug for a given protein. Albumin con- of drug interaction). Elevation of the ntration in plasma amounts to free concentration of the displaced drug 4.6g/100 mL or 0.6 mM, and thus pr means increased effectiveness and ac- vides a very high binding capacity(two celerated elimination. hibit per molecule). As a rule, drugs ex- decrease in the concentration of 10-5-10-3M)for plasma proteins than drome, poor general condition) leads to altered pharmacokinetics of drugs that tors). In the range of therapeutically re oncentrations, protein binding o rugs increases linearly with con- are substrates for transport carriers can ion(exceptions: salicylate and be cleared from blood at great velocity. certain sulfonamides g, P-aminohippurate by the renal tu- The albumin molecule has differen ule and sulfobromopht ver. Clearance rates of these substanc- ands, but van der waals contribute(p. 58). The extent patic blood flow. orrelates with drug hydrophobicity (repulsion of drug by wate stantaneous and reversible. ie. an esponding change in the concentration f bound drug. Protein binding is of al total plasma concentration(say, ng/mL) the effective concentration will e 90 ng/mL for a drug 10% bound to rotein, but 1 ng/mL for a drug 99% bound to protein. The reduction in con- nding affects not only the of the effect but also biotransfor- (e., in the liver) and elimina- tion in the kidney, because only free LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license

Binding to Plasma Proteins Having entered the blood, drugs may bind to the protein molecules that are present in abundance, resulting in the formation of drug-protein complexes. Protein binding involves primarily al￾bumin and, to a lesser extent, β-globu￾lins and acidic glycoproteins. Other plasma proteins (e.g., transcortin, trans￾ferrin, thyroxin-binding globulin) serve specialized functions in connection with specific substances. The degree of binding is governed by the concentra￾tion of the reactants and the affinity of a drug for a given protein. Albumin con￾centration in plasma amounts to 4.6 g/100 mL or O.6 mM, and thus pro￾vides a very high binding capacity (two sites per molecule). As a rule, drugs ex￾hibit much lower affinity (KD approx. 10–5 –10–3 M) for plasma proteins than for their specific binding sites (recep￾tors). In the range of therapeutically rel￾evant concentrations, protein binding of most drugs increases linearly with con￾centration (exceptions: salicylate and certain sulfonamides). The albumin molecule has different binding sites for anionic and cationic li￾gands, but van der Waals’ forces also contribute (p. 58). The extent of binding correlates with drug hydrophobicity (repulsion of drug by water). Binding to plasma proteins is in￾stantaneous and reversible, i.e., any change in the concentration of unbound drug is immediately followed by a cor￾responding change in the concentration of bound drug. Protein binding is of great importance, because it is the con￾centration of free drug that determines the intensity of the effect. At an identi￾cal total plasma concentration (say, 100 ng/mL) the effective concentration will be 90 ng/mL for a drug 10 % bound to protein, but 1 ng/mL for a drug 99 % bound to protein. The reduction in con￾centration of free drug resulting from protein 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 on plasma 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 intensity of the effect is reduced. If two substanc￾es have affinity for the same binding site on the albumin molecule, they may compete for that site. One drug may dis￾place another from its binding site and thereby elevate the free (effective) con￾centration of the displaced drug (a form of drug interaction). Elevation of the free concentration of the displaced drug means increased effectiveness and ac￾celerated elimination. A decrease in the concentration of albumin (liver disease, nephrotic syn￾drome, poor general condition) leads to altered pharmacokinetics of drugs that are highly bound to albumin. Plasma protein-bound drugs that are substrates for transport carriers can be cleared from blood at great velocity, e.g., p-aminohippurate by the renal tu￾bule and sulfobromophthalein by the liver. Clearance rates of these substanc￾es can be used to determine renal or he￾patic blood flow. 30 Distribution in the Body Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license

Distribution in the Body 31 ∈D Drug is to plasma oteins Effect Biotransformation enal elimination Plasma concentration Plasma concentration A Importance of protein binding for intensity and duration of drug effect LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license

Distribution in the Body 31 Renal elimination Biotransformation Effector cell Effect A. Importance of protein binding for intensity and duration of drug effect Drug is not bound to plasma proteins Drug is strongly bound to plasma proteins Effector cell Effect Biotransformation Renal elimination Time Plasma concentration Time Plasma concentration Bound drug Free drug Free drug Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license

32 Drug Elimination The Liver as an Excretory Organ As the chief organ of drug biotransfor- drugs are more rapidly taken up from nation, the liver is richly supplied wit ne blood into hepatocytes and more blood, of which 1100 mL is received readily gain access to mixed-functio nrough the portal vein and 350 mL For instance, a drug having lipophilicity nrough the hepatic artery, comprisin heyl ring)(B)can be hydroxylated content of hepatic vessels and sinusoids and, thus, become more hydrophilic amounts to 500 mL. Due to the widen-(Phase I reaction, p. 34). Besides ox ng of the portal lumen, intrahepati ases, sER also contains reductases and lood flow decelerates(A). Moreover, glucuronyl transferases. The latter cor soids (p. 24)contains pores large carboxyl, amine, and amide groups(p. gh to permit proteins. Thus, blood and hepatic paren- phase I metabolism(Phase ll conjuga- tion). Phase I and Phase Il metabolite contact and intensive exe can be transported back into the blood probably via a gradient-dependent ively secreted into bile. faces abutting Disse's space e hepatocyte secretes bili fluid into the bile canaliculi(dark zepine, rifampicin results in a prolp). n ranes(cf. C and are sealed off from the blood spaces by This enzyme induction, a load-deper tight junctions. Secretory activity in the dent hypertrophy, affects equally all en patocytes results in movement of zymes localized on sER membranes. En fluid towards the canalicular space(A). zyme induction leads to accelerated The hepatocyte has an abundance of en- biotransformation, not only of the in zymes carrying out metabolic functions. ducing agent but also of other drugs(a These are localized in part in mitch orm of drug interaction). With contin action velocity, maximally 2-3 fold, that Enzymes of the sER play a most disappears after removal of the induc- ortant role in drug biotransformation. ing agent. At this site, molecular oxygen is used in oxidative reactions. Because these en- or oxidative cleavage of-N-C-. nds, they are referred to as"mixed- function"oxidases or hydroxylases. The essential component nis enzyne oxidized state binds drug substrates(R H). The Fe -P450-RH binary complex is first reduced by NADPh, then forms the plex, O2-Fe-P450-RH ch accepts a second electron and fi- disintegrates into Fe-P450, one quivalent of H20, and hydroxylated LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license

The Liver as an Excretory Organ As the chief organ of drug biotransfor￾mation, the liver is richly supplied with blood, of which 1100 mL is received each minute from the intestines through the portal vein and 350 mL through the hepatic artery, comprising nearly 1/3 of cardiac output. The blood content of hepatic vessels and sinusoids amounts to 500 mL. Due to the widen￾ing of the portal lumen, intrahepatic blood flow decelerates (A). Moreover, the endothelial lining of hepatic sinu￾soids (p. 24) contains pores large enough to permit rapid exit of plasma proteins. Thus, blood and hepatic paren￾chyma are able to maintain intimate contact and intensive exchange of sub￾stances, which is further facilitated by microvilli covering the hepatocyte sur￾faces abutting Disse’s spaces. The hepatocyte secretes biliary fluid into the bile canaliculi (dark green), tubular intercellular clefts that are sealed off from the blood spaces by tight junctions. Secretory activity in the hepatocytes results in movement of fluid towards the canalicular space (A). 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 the rough (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 in oxidative reactions. Because these en￾zymes can catalyze either hydroxylation or oxidative cleavage of -N-C- or -O-C￾bonds, they are referred to as “mixed￾function” oxidases or hydroxylases. The essential component of this enzyme system is cytochrome P450, which in its oxidized state binds drug substrates (R￾H). The FeIII-P450-RH binary complex is first reduced by NADPH, then forms the ternary complex, O2-FeII-P450-RH, which accepts a second electron and fi￾nally disintegrates into FeIII-P450, one equivalent of H2O, and hydroxylated drug (R-OH). Compared with hydrophilic drugs not undergoing transport, lipophilic drugs are more rapidly taken up from the blood into hepatocytes and more readily gain access to mixed-function oxidases embedded in sER membranes. For instance, a drug having lipophilicity by virtue of an aromatic substituent (phenyl ring) (B) can be hydroxylated and, thus, become more hydrophilic (Phase I reaction, p. 34). Besides oxi￾dases, sER also contains reductases and glucuronyl transferases. The latter con￾jugate glucuronic acid with hydroxyl, carboxyl, amine, and amide groups (p. 38); hence, also phenolic products of phase I metabolism (Phase II conjuga￾tion). Phase I and Phase II metabolites can be transported back into the blood — probably via a gradient-dependent carrier — 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 (cf. C and D). This enzyme induction, a load-depen￾dent hypertrophy, affects equally all en￾zymes localized on sER membranes. En￾zyme induction leads to accelerated biotransformation, not only of the in￾ducing agent but also of other drugs (a form of drug interaction). With contin￾ued exposure, induction develops in a few days, resulting in an increase in re￾action velocity, maximally 2–3fold, that disappears after removal of the induc￾ing agent. 32 Drug Elimination Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license