Drug Elimination X

Lipophilic drugs that are converted
in the liver to hydrophilic metabolites
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 metabolite
is rapid, only a portion of the
absorbed drug enters the systemic circulation
in unchanged form, the remainder
having undergone presystemic
(first-pass) elimination. When biotransformation
is rapid, oral administration
of the drug is impossible (e.g.,
glyceryl trinitate). Parenteral or,
alternatively, sublingual, intranasal, or
transdermal administration is then required
in order to bypass the liver. Irrespective
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 presystemic
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 diminishes
the bioavailability of a drug after its
oral administration. Absolute bioavailability
= systemically available amount/
dose administered; relative bioavailability
= availability of a drug contained
in a test preparation with reference to a
standard preparation.

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Drug Elimination IX

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 lipid
bilayer membrane — and fat constitute
apolar media. Most polar substances
are readily dissolved in aqueous media
(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 liver
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 hepatic
biotransforming enzymes. The unchanged
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 lipophilicity),
hence the entire amount
present in plasma is available for glomerular
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 access
to all cells, including metabolically
active liver cells, it is likely to be retained
in the organism. The portion filtered
during glomerular passage will be
reabsorbed from the tubules. Reabsorption
will be nearly complete, because
the free concentration of a lipophilic
drug in plasma is low (lipophilic substances
are usually largely proteinbound).
The situation portrayed for a
lipophilic non-metabolizable drug
would seem undesirable because pharmacotherapeutic
measures once initiated
would be virtually irreversible (poor
control over blood concentration).

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Drug Elimination VIII

During passage down the renal tubule,
urinary volume shrinks more than
100-fold; accordingly, there is a corresponding
concentration of filtered drug
or drug metabolites . 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 gradient
will favor reabsorption of the filtered
molecules. In this case, reabsorption
is not based on an active process
but results instead from passive diffusion.
Accordingly, for protonated substances,
the extent of reabsorption is
dependent upon urinary pH or the degree
of dissociation. The degree of dissociation
varies as a function of the urinary
pH and the pKa, which represents
the pH value at which half of the substance
exists in protonated (or unprotonated)
form. This relationship is graphically
illustrated with the example of
a protonated amine having a pKa 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 lumen
in accordance with the resulting
concentration gradient. If the pKa of 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 pKa 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 substances
in order to hasten elimination of
the toxin (alkalinization ! phenobarbital;
acidification !amphetamine).

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Drug Elimination VII

The Kidney as Excretory Organ
Most drugs are eliminated in urine either
chemically unchanged or as metabolites.
The kidney permits elimination
because the vascular wall structure in
the region of the glomerular capillaries
allows unimpeded passage of blood
solutes having molecular weights (MW)
<> 70000. With
few exceptions, therapeutically used
drugs and their metabolites have much
smaller molecular weights and can,
therefore, undergo glomerular filtration,
i.e., pass from blood into primary
urine. Separating the capillary endothelium
from the tubular epithelium, the
basal membrane consists of charged
glycoproteins and acts as a filtration
barrier for high-molecular-weight substances.
The relative density of this barrier
depends on the electrical charge of
molecules that attempt to permeate it.
Apart from glomerular filtration
, 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, energyconsuming
transport systems. These
transport systems have a limited capacity.
When several substrates are present
simultaneously, competition for the
carrier may occur .

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Drug Elimination VI

Conjugations
The most important of phase II conjugation
reactions is glucuronidation. This
reaction does not proceed spontaneously,
but requires the activated form of
glucuronic acid, namely glucuronic acid
uridine diphosphate. Microsomal glucuronyl
transferases link the activated
glucuronic acid with an acceptor molecule.
When the latter is a phenol or alcohol,
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 sulfotransferases
conjugate activated sulfate (3’-
phosphoadenine-5’-phosphosulfate)
with alcohols and phenols. The conjugates
are acids, as in the case of glucuronides.
In this respect, they differ from
conjugates formed by acetyltransferases
from activated acetate (acetylcoenzyme
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 acceptor
and the amino group of the donor
molecule (e.g., formation of salicyluric
acid from salicylic acid and glycine).
The acidic group of glycine or glutamine
remains free.

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Drug Elimination V

Enterohepatic Cycle
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 sulfuric
acid (shown in B for salicylic acid
and deacetylated bisacodyl, respectively)
or to other organic acids. At the pH of
body fluids, these acids are predominantly
ionized; the negative charge confers
high polarity upon the conjugated
drug molecule and, hence, low membrane
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 enterohepatic
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 kidney
and are excreted in urine because
their decreased lipophilicity prevents
tubular reabsorption.
Drugs that are subject to enterohepatic
cycling are, therefore, excreted
slowly. Pertinent examples include digitoxin
and acidic nonsteroidal anti-inflammatory
agents .

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Drug Elimination IV

Reduction reactions may occur at
oxygen or nitrogen atoms. Keto-oxygens
are converted into a hydroxyl
group, as in the reduction of the prodrugs
cortisone and prednisone to the
active glucocorticoids cortisol and prednisolone,
respectively. N-reductions occur
in azo- or nitro-compounds (e.g., nitrazepam).
Nitro groups can be reduced
to amine groups via nitroso and hydroxylamino
intermediates. Likewise, dehalogenation
is a reductive process involving
a carbon atom (e.g., halothane).
Methylations are catalyzed by a
family of relatively specific methyltransferases
involving the transfer of
methyl groups to hydroxyl groups (Omethylation
as in norepinephrine [noradrenaline])
or to amino groups (Nmethylation
of norepinephrine, histamine,
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 bioinactivation.
Thus, paraoxon (E600)
formed in the organism from parathion
(E605) is the actual active agent .

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Drug Elimination III

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. Hydroxylations
may involve alkyl substituents
(e.g., pentobarbital) or aromatic
ring systems (e.g., propranolol). In both
cases, products are formed that are conjugated
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 hydroxylamines
(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 hepatotoxic
and possibly carcinogenic.
The second type of oxidative biotransformation
comprises dealkylations.
In the case of primary or secondary
amines, dealkylation of an alkyl
group starts at the carbon adjacent to
the nitrogen; in the case of tertiary
amines, with hydroxylation of the nitrogen
(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 analogous
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

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Drug Elimination II

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Drug Elimination II

Ester hydrolysis does not invariably
lead to inactive metabolites, as exemplified
by acetylsalicylic acid. The cleavage
product, salicylic acid, retains pharmacological
activity. In certain cases,
drugs are administered in the form of
esters in order to facilitate absorption
(enalapril ! enalaprilate; testosterone
undecanoate ! testosterone) or to reduce
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 hydrolysis
in the blood.
Some drugs possessing amide
bonds, such as prilocaine, and of course,
peptides, can be hydrolyzed by peptidases
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 inhibited,
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 histidylleucine.
Hydrolysis is catalyzed by “angiotensin-
converting enzyme” (ACE). Peptide
analogues such as captopril (p. 124)
block this enzyme. Angiotensin II is degraded
by angiotensinase A, which clips
off the N-terminal asparagine residue.
The product, angiotensin III, lacks vasoconstrictor
activity.

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Drug Elimination I

The Liver as an Excretory Organ
As the chief organ of drug biotransformation,
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 widening
of the portal lumen, intrahepatic
blood flow decelerates . Moreover,
the endothelial lining of hepatic sinusoids
contains pores large
enough to permit rapid exit of plasma
proteins. Thus, blood and hepatic parenchyma
are able to maintain intimate
contact and intensive exchange of substances,
which is further facilitated by
microvilli covering the hepatocyte surfaces
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.
The hepatocyte has an abundance of enzymes
carrying out metabolic functions.
These are localized in part in mitochondria,
in part on the membranes of the
rough (rER) or smooth (sER) endoplasmic
reticulum.

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