Tài liệu Color Atlas of Pharmacology (Part 4): Drug Elimination doc

The latter con-jugate glucuronic acid with hydroxyl, carboxyl, amine, and amide groups p.. En-zyme induction leads to accelerated biotransformation, not only of the in-ducing agent but a

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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 1/3of 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-depdent 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

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D Hepatocyte after

D phenobarbital administration

A Flow patterns in portal vein, Disse’s space, and hepatocyte

C Normal hepatocyte

Gall-bladder

Portal vein

sER rER

Phase II-metabolite

Biliary capillary

Glucuronide Carrier

Phase I-metabolite

B Fate of drugs undergoing

B hepatic hydroxylation

Biliary capillary

Intestine

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Biotransformation of Drugs

Many drugs undergo chemical

modifi-cation in the body (biotransformation).

Most frequently, this process entails a

loss of biological activity and an

in-crease in hydrophilicity (water

solubil-ity), thereby promoting elimination via

the renal route (p 40) Since rapid drug

elimination improves accuracy in

titrat-ing the therapeutic concentration, drugs

are often designed with built-in weak

links Ester bonds are such links, being

subject to hydrolysis by the ubiquitous

esterases Hydrolytic cleavages, along

with oxidations, reductions, alkylations,

and dealkylations, constitute Phase I

re-actions of drug metabolism These

reac-tions subsume all metabolic processes

apt to alter drug molecules chemically

and take place chiefly in the liver In

Phase II (synthetic) reactions,

conju-gation products of either the drug itself

or its Phase I metabolites are formed, for

instance, with glucuronic or sulfuric

ac-id (p 38)

The special case of the endogenous

transmitter acetylcholine illustrates

well the high velocity of ester

hydroly-sis Acetylcholine is broken down at its

sites of release and action by

acetylchol-inesterase (pp 100, 102) so rapidly as to

negate its therapeutic use Hydrolysis of

other esters catalyzed by various

este-rases is slower, though relatively fast in

comparison with other

biotransforma-tions The local anesthetic, procaine, is a

case in point; it exerts its action at the

site of application while being largely

devoid of undesirable effects at other

lo-cations because it is inactivated by

hy-drolysis during absorption from its site

of application

Ester hydrolysis does not invariably

lead to inactive metabolites, as

exempli-fied by acetylsalicylic acid The cleavage

product, salicylic acid, retains

phar-macological activity In certain cases,

drugs are administered in the form of

esters in order to facilitate absorption

(enalapril ! enalaprilate; testosterone

undecanoate ! testosterone) or to

re-duce irritation of the gastrointestinal

mucosa (erythromycin succinate ! erythromycin) In these cases, the ester itself is not active, but the cleavage product is Thus, an inactive precursor

or prodrug is applied, formation of the

active molecule occurring only after hy-drolysis in the blood

Some drugs possessing amide bonds, such as prilocaine, and of course, peptides, can be hydrolyzed by pepti-dases and inactivated in this manner Peptidases are also of pharmacological interest because they are responsible for the formation of highly reactive cleavage products (fibrin, p 146) and potent mediators (angiotensin II, p 124; bradykinin, enkephalin, p 210) from biologically inactive peptides Peptidases exhibit some substrate selectivity and can be selectively inhib-ited, as exemplified by the formation of angiotensin II, whose actions inter alia include vasoconstriction Angiotensin II

is formed from angiotensin I by cleavage

of the C-terminal dipeptide histidylleu-cine Hydrolysis is catalyzed by “angio-tensin-converting enzyme” (ACE) Pep-tide analogues such as captopril (p 124) block this enzyme Angiotensin II is de-graded by angiotensinase A, which clips off the N-terminal asparagine residue The product, angiotensin III, lacks vaso-constrictor activity

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A Examples of chemical reactions in drug biotransformation (hydrolysis)

Acetylcholine

Converting enzyme

Angiotensinase Procaine

N-Propylalanine Toluidine Acetic acid Salicylic acid

Diethylaminoethanol

p-Aminobenzoic acid

Acetic acid

Choline

Angiotensin III Angiotensin II

Angiotensin I

Esterases Ester Peptidases Amides Anilides

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Oxidation reactions can be divided

into two kinds: those in which oxygen is

incorporated into the drug molecule,

and those in which primary oxidation

causes part of the molecule to be lost

The former include hydroxylations,

epoxidations, and sulfoxidations

Hy-droxylations may involve alkyl

substitu-ents (e.g., pentobarbital) or aromatic

ring systems (e.g., propranolol) In both

cases, products are formed that are

con-jugated to an organic acid residue, e.g.,

glucuronic acid, in a subsequent Phase II

reaction

Hydroxylation may also take place

at nitrogen atoms, resulting in

hydroxyl-amines (e.g., acetaminophen) Benzene,

polycyclic aromatic compounds (e.g.,

benzopyrene), and unsaturated cyclic

carbohydrates can be converted by

mono-oxygenases to epoxides, highly

reactive electrophiles that are

hepato-toxic and possibly carcinogenic

The second type of oxidative

bio-transformation comprises

dealkyla-tions In the case of primary or

secon-dary amines, dealkylation of an alkyl

group starts at the carbon adjacent to

the nitrogen; in the case of tertiary

amines, with hydroxylation of the

nitro-gen (e.g., lidocaine) The intermediary

products are labile and break up into the

dealkylated amine and aldehyde of the

alkyl group removed O-dealkylation

and S-dearylation proceed via an analo-gous mechanism (e.g., phenacetin and azathioprine, respectively)

Oxidative deamination basically

resembles the dealkylation of tertiary amines, beginning with the formation of

a hydroxylamine that then decomposes into ammonia and the corresponding aldehyde The latter is partly reduced to

an alcohol and partly oxidized to a car-boxylic acid

Reduction reactions may occur at

oxygen or nitrogen atoms Keto-oxy-gens are converted into a hydroxyl group, as in the reduction of the pro-drugs cortisone and prednisone to the active glucocorticoids cortisol and pred-nisolone, respectively N-reductions oc-cur in azo- or nitro-compounds (e.g., ni-trazepam) Nitro groups can be reduced

to amine groups via nitroso and hydrox-ylamino intermediates Likewise, deha-logenation is a reductive process involv-ing a carbon atom (e.g., halothane, p 218)

Methylations are catalyzed by a

family of relatively specific methyl-transferases involving the transfer of methyl groups to hydroxyl groups (O-methylation as in norepinephrine [nor-adrenaline]) or to amino groups (N-methylation of norepinephrine, hista-mine, or serotonin)

In thio compounds, desulfuration

results from substitution of sulfur by oxygen (e.g., parathion) This example again illustrates that biotransformation

is not always to be equated with bio-inactivation Thus, paraoxon (E600) formed in the organism from parathion (E605) is the actual active agent (p 102)

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A Examples of chemical reactions in drug biotransformation

Pentobarbital

Hydroxylation

Propranolol

Azathioprine

Parathion

Desulfuration

Methylation

Nitrazepam

Benzpyrene Chlorpromazine

Norepinephrine

Epoxidation

Sulfoxidation

Hydroxyl-amine

Dealkylation

Acetaminophen

N-Dealkylation

O-Dealkylation

S-Dealkylation

O-Methylation

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Enterohepatic Cycle (A)

After an orally ingested drug has been

absorbed from the gut, it is transported

via the portal blood to the liver, where it

can be conjugated to glucuronic or

sul-furic acid (shown in B for salicylic acid

and deacetylated bisacodyl,

respective-ly) or to other organic acids At the pH of

body fluids, these acids are

predomi-nantly ionized; the negative charge

con-fers high polarity upon the conjugated

drug molecule and, hence, low

mem-brane penetrability The conjugated

products may pass from hepatocyte into

biliary fluid and from there back into

the intestine O-glucuronides can be

cleaved by bacterial !-glucuronidases in

the colon, enabling the liberated drug

molecule to be reabsorbed The

entero-hepatic cycle acts to trap drugs in the

body However, conjugated products

enter not only the bile but also the

blood Glucuronides with a molecular

weight (MW) > 300 preferentially pass

into the blood, while those with MW >

300 enter the bile to a larger extent

Glucuronides circulating in the blood

undergo glomerular filtration in the

kid-ney and are excreted in urine because

their decreased lipophilicity prevents

tubular reabsorption

Drugs that are subject to

enterohe-patic cycling are, therefore, excreted

slowly Pertinent examples include

digi-toxin and acidic nonsteroidal

anti-in-flammatory agents (p 200)

Conjugations (B)

The most important of phase II

conjuga-tion reacconjuga-tions is glucuronidaconjuga-tion This

reaction does not proceed

spontaneous-ly, but requires the activated form of

glucuronic acid, namely glucuronic acid

uridine diphosphate Microsomal

glucu-ronyl transferases link the activated

glucuronic acid with an acceptor

mole-cule When the latter is a phenol or

alco-hol, an ether glucuronide will be

formed In the case of carboxyl-bearing

molecules, an ester glucuronide is the

result All of these are O-glucuronides

Amines may form N-glucuronides that, unlike O-glucuronides, are resistant to bacterial !-glucuronidases

Soluble cytoplasmic

sulfotrans-ferases conjugate activated sulfate

(3’-phosphoadenine-5’-phosphosulfate) with alcohols and phenols The conju-gates are acids, as in the case of glucuro-nides In this respect, they differ from conjugates formed by

acetyltransfe-rases from activated acetate

(acetyl-coenzyme A) and an alcohol or a phenol Acyltransferases are involved in the

conjugation of the amino acids glycine

or glutamine with carboxylic acids In

these cases, an amide bond is formed between the carboxyl groups of the ac-ceptor and the amino group of the do-nor molecule (e.g., formation of salicyl-uric acid from salicylic acid and glycine) The acidic group of glycine or glutamine remains free

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A Enterohepatic cycle

B Conjugation reactions

UDP-"-Glucuronic acid

3'-Phosphoadenine-5'-phosphosulfate

Active moiety of bisacodyl Salicylic acid

Biliary elimination

Enteral absorption

Renal

elimination Lipophilicdrug

Sinusoid

Hepatocyte

Biliary capillary

Conjugation with glucuronic acid

Portal vein

Hydrophilic conjugation product

1

3

5 7

8

4

E n

t e ro

h e p a t i c c i rcula t i o n 6

2

Deconjugation

by microbial

!-glucuronidase

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The Kidney as Excretory Organ

Most drugs are eliminated in urine

ei-ther chemically unchanged or as

metab-olites The kidney permits elimination

because the vascular wall structure in

the region of the glomerular capillaries

(B) allows unimpeded passage of blood

solutes having molecular weights (MW)

< 5000 Filtration diminishes

progres-sively as MW increases from 5000 to

70000 and ceases at MW > 70000 With

few exceptions, therapeutically used

drugs and their metabolites have much

smaller molecular weights and can,

therefore, undergo glomerular

filtra-tion, i.e., pass from blood into primary

urine Separating the capillary

endothe-lium from the tubular epitheendothe-lium, the

basal membrane consists of charged

glycoproteins and acts as a filtration

barrier for high-molecular-weight

sub-stances The relative density of this

bar-rier depends on the electrical charge of

molecules that attempt to permeate it

Apart from glomerular filtration

(B), drugs present in blood may pass

into urine by active secretion Certain

cations and anions are secreted by the

epithelium of the proximal tubules into

the tubular fluid via special,

energy-consuming transport systems These

transport systems have a limited

capac-ity When several substrates are present

simultaneously, competition for the

carrier may occur (see p 268)

During passage down the renal

tu-bule, urinary volume shrinks more than

100-fold; accordingly, there is a

corre-sponding concentration of filtered drug

or drug metabolites (A) The resulting

concentration gradient between urine

and interstitial fluid is preserved in the

case of drugs incapable of permeating

the tubular epithelium However, with

lipophilic drugs the concentration

gra-dient will favor reabsorption of the

fil-tered molecules In this case,

reabsorp-tion is not based on an active process

but results instead from passive

diffu-sion Accordingly, for protonated

sub-stances, the extent of reabsorption is

dependent upon urinary pH or the

de-gree of dissociation The dede-gree of disso-ciation varies as a function of the uri-nary pH and the pKa, which represents the pH value at which half of the sub-stance exists in protonated (or unproto-nated) form This relationship is

graphi-cally illustrated (D) with the example of

a protonated amine having a pKaof 7.0

In this case, at urinary pH 7.0, 50 % of the amine will be present in the protonated, hydrophilic, membrane-impermeant form (blue dots), whereas the other half, representing the uncharged amine (orange dots), can leave the tubular lu-men in accordance with the resulting concentration gradient If the pKaof an amine is higher (pKa= 7.5) or lower (pKa

= 6.5), a correspondingly smaller or larger proportion of the amine will be present in the uncharged, reabsorbable form Lowering or raising urinary pH by half a pH unit would result in analogous changes for an amine having a pKaof 7.0

The same considerations hold for acidic molecules, with the important difference that alkalinization of the urine (increased pH) will promote the deprotonization of -COOH groups and thus impede reabsorption Intentional alteration in urinary pH can be used in intoxications with proton-acceptor sub-stances in order to hasten elimination of the toxin (alkalinization ! phenobarbi-tal; acidification ! amphetamine)

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C Active secretion

180 L

Primary

urine

Glomerular filtration

of drug

Concentration

of drug

in tubule

1.2 L

Final

urine

–

+

+ +

+

-Tubular

transport

system for

Cations

Anions

Blood Plasma-protein Endothelium Basal membrane Drug

Epithelium

Primary urine

pH = 7.0

pH = 7.0 pH of urine

%

6 6.5 7 7.5 8

100

50

pKa = 7.5

%

6 6.5 7 7.5 8

100

50

pKa = 6.5

D Tubular reabsorption

A Filtration and concentration

B Glomerular filtration

pKa of substance

%

6 6.5 7 7.5 8

100

50

pKa = 7.0

+

Tiêu đề	The Liver as an Excretory Organ
Tác giả	Lüllmann
Chuyên ngành	Pharmacology
Thể loại	Chapter
Năm xuất bản	2000

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Số trang	12
Dung lượng	482 KB