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

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 Fe
III
-P450-RH binary complex is
first reduced by NADPH, then forms the
ternary complex, O
2
-Fe
II
-P450-RH,
which accepts a second electron and fi-
nally disintegrates into Fe
III

-P450, one
equivalent of H
2
O, 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
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Drug Elimination 33
D. Hepatocyte after
D. phenobarbital administration
A. Flow patterns in portal vein, Disse’s space, and hepatocyte
C. Normal hepatocyte
Hepatocyte Disse´s space
Gall-bladder
Portal vein
sER
rER
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 Ǟ enalaprilate; testosterone
undecanoate Ǟ testosterone) or to re-
duce irritation of the gastrointestinal
mucosa (erythromycin succinate Ǟ
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.
34 Drug Elimination
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Drug Elimination 35
A. Examples of chemical reactions in drug biotransformation (hydrolysis)
Acetylcholine
Converting
enzyme
Angiotensinase
Procaine
Acetylsalicylic acid Prilocaine
N-Propylalanine ToluidineAcetic 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).
36 Drug Elimination
Desalkylierung
3
N
R
1
R
2
H
O
CH
3
H C
O
2
+
N

R
1
R
2
CH
3
OH
N
R
1
R
2
CH
Desalkylierung
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Drug Elimination 37
A. Examples of chemical reactions in drug biotransformation
Pentobarbital
Hydroxylation
Propranolol
Lidocaine Phenacetin
Azathioprine
Parathion
Desulfuration
Methylation
Nitrazepam
Reduction
Oxidation
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 reactions is glucuronidation. 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.
38 Drug Elimination
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Drug Elimination 39
A. Enterohepatic cycle

B. Conjugation reactions
UDP-"-Glucuronic acid
Glucuronyl-
transferase
Sulfo-
transferase
3'-Phosphoadenine-5'-phosphosulfate
Active moiety of bisacodylSalicylic acid
Biliary
elimination
Enteral
absorption
Renal
elimination
Lipophilic
drug
Sinusoid
Hepatocyte
Biliary capillary
Conjugation with
glucuronic acid
Portal vein
Hydrophilic
conjugation product
1
3
5
7
8
4

E
n
t
e
r
o
h
e
p
a
t
i
c
c
i
r
c
u
l
a
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 epithelium, 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 degree of disso-
ciation varies as a function of the uri-
nary pH and the pK
a
, 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 pK
a
of 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 pK
a
of an
amine is higher (pK
a
= 7.5) or lower (pK
a
= 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 pK
a
of
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 Ǟ phenobarbi-
tal; acidification Ǟ amphetamine).
40 Drug Elimination
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Drug Elimination 41
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
pK
a
= 7.5
%
6 6.5 7 7.5 8
100
50
pK
a
= 6.5
D. Tubular reabsorption
A. Filtration and concentration
B. Glomerular filtration
pK
a
of substance
%
6 6.5 7 7.5 8
100
50
pK
a
= 7.0
+
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Elimination of Lipophilic and
Hydrophilic Substances

The terms lipophilic and hydrophilic
(or hydro- and lipophobic) refer to the
solubility of substances in media of low
and high polarity, respectively. Blood
plasma, interstitial fluid, and cytosol are
highly polar aqueous media, whereas
lipids — at least in the interior of the lip-
id bilayer membrane — and fat consti-
tute apolar media. Most polar substanc-
es are readily dissolved in aqueous me-
dia (i.e., are hydrophilic) and lipophilic
ones in apolar media. A hydrophilic
drug, on reaching the bloodstream,
probably after a partial, slow absorption
(not illustrated), passes through the liv-
er unchanged, because it either cannot,
or will only slowly, permeate the lipid
barrier of the hepatocyte membrane
and thus will fail to gain access to hepat-
ic biotransforming enzymes. The un-
changed drug reaches the arterial blood
and the kidneys, where it is filtered.
With hydrophilic drugs, there is little
binding to plasma proteins (protein
binding increases as a function of li-
pophilicity), hence the entire amount
present in plasma is available for glo-
merular filtration. A hydrophilic drug is
not subject to tubular reabsorption and
appears in the urine. Hydrophilic drugs

undergo rapid elimination.
If a lipophilic drug, because of its
chemical nature, cannot be converted
into a polar product, despite having ac-
cess to all cells, including metabolically
active liver cells, it is likely to be re-
tained in the organism. The portion fil-
tered during glomerular passage will be
reabsorbed from the tubules. Reabsorp-
tion will be nearly complete, because
the free concentration of a lipophilic
drug in plasma is low (lipophilic sub-
stances are usually largely protein-
bound). The situation portrayed for a
lipophilic non-metabolizable drug
would seem undesirable because phar-
macotherapeutic measures once initiat-
ed would be virtually irreversible (poor
control over blood concentration).
Lipophilic drugs that are convert-
ed in the liver to hydrophilic metab-
olites permit better control, because the
lipophilic agent can be eliminated in
this manner. The speed of formation of
hydrophilic metabolite determines the
drug’s length of stay in the body.
If hepatic conversion to a polar me-
tabolite is rapid, only a portion of the
absorbed drug enters the systemic cir-
culation in unchanged form, the re-

mainder having undergone presystem-
ic (first-pass) elimination. When bio-
transformation is rapid, oral adminis-
tration of the drug is impossible (e.g.,
glyceryl trinitate, p. 120). Parenteral or,
alternatively, sublingual, intranasal, or
transdermal administration is then re-
quired in order to bypass the liver. Irre-
spective of the route of administration,
a portion of administered drug may be
taken up into and transiently stored in
lung tissue before entering the general
circulation. This also constitutes pre-
systemic elimination.
Presystemic elimination refers to
the fraction of drug absorbed that is
excluded from the general circulation
by biotransformation or by first-pass
binding.
Presystemic elimination diminish-
es the bioavailability of a drug after its
oral administration. Absolute bioavail-
ability = systemically available amount/
dose administered; relative bioavail-
ability = availability of a drug contained
in a test preparation with reference to a
standard preparation.
42 Drug Elimination
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Drug Elimination 43
A. Elimination of hydrophilic and hydrophobic drugs
Hydrophilic drug Lipophilic drug
no metabolism
Lipophilic drug Lipophilic drug
Renal
excretion
Excretion
impossible
Renal excretion
of metabolite
Renal excretion
of metabolite
Slow conversion
in liver to
hydrophilic metabolite
Rapid and complete
conversion in liver to
hydrophilic metabolite
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