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

-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).

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

(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-

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

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

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

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

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
Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

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-

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

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

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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