Drug elimination

Drug elimination is the irreversible loss of drug

from the body.

It occurs by two processes: metabolism and

excretion.

Metabolism involves enzymic conversion of

one chemical entity to another within the body,
whereas excretion consists of elimination from
the body of chemically unchanged drug or its
metabolites.
Introduction
Renal excretion terminates the actions of
relatively few drugs, such as:
 Small, hydrophilic drugs
 Those remain fully or nearly fully
ionized at physiological pH
 Those are not protein bound

However, most pharmacologically active

molecules tend to be:
 Lipophilic
 Remain unionized or only partially
ionized at physiological pH
 Often bound strongly to plasma proteins
 These are not good candidates for renal
elimination. Metabolism is the more important
mechanism of termination for most drugs.
Lipophilic, unionized or bound drugs would
remain in the body for prolonged periods if their
actions were not terminated by some alternate
process.
For example- Pentobarbital
Highly lipophilic anesthetic
agent would exert its
pharmacological effect for 100
years if it weren’t for drug
metabolism.
Drug metabolism
Drug metabolism refers to the biochemical
changes that drugs undergo in the body,
leading to the formation of different metabolites
with different effects.
Rarely is only one metabolite produced
from a single drug.
In general, most drugs are metabolized
into molecules that are more water soluble.
Usually, drug metabolites are less active
pharmacologically than the parent compound.
Possible types of metabolites
a. Inactive metabolites:
Atropine → Tropic acid + Tropine
6-mercaptopurine → 6-mercapturic acid
(Active drug) (Inactive)

b. Metabolites that retain similar activity:

Propranolol → Hydroxypropranolol
(Active) (Active)
Codeine → Morphine
(Active) (More active)
c. Metabolites with altered activity:
Retinoic acid (vitamin A) → Isoretinoic acid
(Anti-acne agent)
Iproniazid → Isoniazid
(Anti-acne agent) (Antitubercular agent)

d. Bioactivated metabolite:
Enalapril → Enalaprilat
(Prodrug) (Potent antihypertensive)
L-Dopa → Dopamine
(Prodrug) (Antiparkinson drug)
Organ sites of drug metabolism
The liver is the major site for drug
metabolism, but specific drugs may undergo
biotransformation in other tissues:

GI mucosa (tyramine, salbutamol)

Kidneys
Skin
Lung (various prostanoids)
Nasal mucosa
Plasma (suxamethonium)
Cellular sites of drug metabolism
» Cytosol or cytoplasm or intracellular fluid
» Mitochondria
» Lysosomes

Kinetics of metabolism
First order kinetics:
Rate of drug metabolism is directly
proportional to the concentration of free drug
and first order kinetics are observed.
This means that a constant fraction of
remaining drug is metabolized per unit time.
 At low doses drug metabolism is first
order, that is proportional to drug dose.
80
70
60 zero order metabolism
(ng/g tissue/min)
Velocity

50
40
30
20
first order metabolism
10
0
0 5 10 15 20 25 30 35 40 45 50 55 60

[Drug] mM
Zero order kinetics:
Rate of drug metabolism is not dependent
on the concentration of free drug and rate of
metabolism remain constant over time.
The enzyme is saturated by a high free-
drug concentration, and the rate of metabolism
remains constant over time. This is called zero
order kinetics. A constant amount of drug is
metabolized per unit time.
At high doses drug (aspirin) metabolism is
zero order, that is constant and independent of
drug dose.
Reactions of drug metabolism
The kidney cannot efficiently eliminate
lipophilic drugs that readily cross cell
membranes and are reabsorbed in the distal
tubules of kidney.
Therefore, lipid-soluble agents must be
metabolized for excretion. Drug metabolism
reactions are divided into two main categories:
Phase I
Phase II
Fig: Nephron
Phase I reaction
Phase I reactions function to convert
lipophilic molecules into more polar molecules
by introducing or unmasking a polar functional
group, such as -OH, -NH2 etc. Phase I reactions
are catabolic.

Phase I metabolism may increase,

decrease, or leave unaltered the drug's
pharmacologic activity.

Common reactions that occur during

metabolism are oxidation, reduction,
hydrolysis.
Phase I reactions utilizing the P450 system
Cytochrome P450 system
Group of 12 closely related enzyme
families in the liver. CYP1, CYP2 and CYP3
metabolize drugs.
The Phase I reactions most frequently
involved in drug metabolism are catalyzed by
the cytochrome P450 system (also called
microsomal mixed function oxidase).
The P450 system is important for the
metabolism of many endogenous compounds
(steroids, lipids, etc.), and for the detoxication
of exogenous substances.
 Cytochrome P-450, designated as CYP, is
composed of many families of heme-containing
isozymes that are located in most cells, but
mainly those in the liver and intestinal tract.
Substrate specificity is very low and have
powerful oxidizing property.

Oxidation by Cytochrome P450 system

e-
The cycle involves four steps:

Oxidized (Fe3+) cytochrome P450 combines with

a drug substrate to form a binary complex.

NADPH donates an electron to the cytochrome

P450 reductase, which in turn reduces the
oxidized cytochrome P450-drug complex.
A second electron is introduced from NADPH via
the same cytochrome P450 reductase, which
serves to reduce molecular oxygen and form
an "activated oxygen"-cytochrome P450-
substrate complex.

This complex in turn transfers "activated"

oxygen to the drug substrate to form the
oxidized product. The potent oxidizing
properties of this activated oxygen permit
oxidation of a large number of substrates.
Drug-drug interactions:
Some drugs can induce the synthesis of
many different CYP isozymes, thereby
accelerating the clearance of substrates of
those metabolic pathways and decreasing their
levels.
Common CYP inducers are: phenobarbital,
rifampin, carbamazepine

Rifampin → ↓ HIV protease inhibitors in plasma

(Antitubercular drug)(saquinavir, ritonavir, indinavir, nelfinavir etc.)
used to treat or prevent infection by viruses
 Some drugs can inhibit the synthesis of
many different CYP isozymes, clearance of
substances can be lowered & their levels
elevated by inhibition of their metabolism.
Common CYP inhibitors are: erythromycin,
ketoconazole, omeprazole

Omeprazole → ↑ warfarin concentration in plasma

(Antiulcerant) (an anticoagulant)
Phase I reactions not involving the P-450 system:
Amine oxidation:
Oxidation of catecholamines or histamine
Alcohol dehydrogenation:
Ethanol oxidation
Hydrolysis:
Hydrolysis of Procain
Phase II
Phase II consists of conjugation reactions.
If the metabolite from Phase I metabolism is
sufficiently polar, it can be excreted by the
kidneys.
However, many metabolites are too
lipophilic to be retained in the kidney tubules.
A subsequent conjugation reaction with an
endogenous substrate, such as glucuronic acid,
sulfuric acid, acetic acid or an amino acid results
in polar, usually more water-soluble compounds
that are most often therapeutically inactive.
Glucuronidation is the most common and the
most important conjugation reaction.
 Neonates are deficient in this conjugating
system making them particularly vulnerable to
drugs such as chloramphenicol.

Drugs already possessing an -OH, -HN2, or

-COOH group may enter Phase II directly, and
become conjugated without prior Phase I
metabolism.

The highly polar drug conjugates may then

be excreted by the kidney.
Phases of drug metabolism
Example of the whole system
Benzene– very lipid soluble compound
First hydroxylated by phase I reactions to
phenol
Hydroxylation doubles (2X) the elimination of
the compound
Phenol is then conjugated with sulfate and
glucuronic acid (phase II)
Resulting compound has an excretion rate
which is 10 to 20 fold greater than benzene

Endogenous substances for conjugation

Glucorinic acid Glycin
Sulfate Acetate
The biotransformation of drugs

Directly Some drugs directly

Enter Phase II
metabolism
Oxidation,
reduction Conjugation
Drug Phase I Phase II products
and/or
hydrolysis

Conjugated drug is
Following Phase I, the drug may usually inactive.
be activated, unchanged,
inactivated.
Summary of drug metabolism:
Phase I reactions often introduce a
reactive group, such as hydroxyl, into the
molecule. This process is known as
'functionalisation'.

This group then serves as the point of

attack for the conjugating system to attach a
substituent such as glucuronide.

Both phases decrease lipid solubility, thus

increasing renal elimination.