Elimination of Drugs

Metabolism

I. F. Benter
Pharmacology & Toxicology
Faculty of Medicine
Kuwait University
 Renal excretion terminates the actions
of relatively few drugs, such as:
 Small drugs
 Those that remain fully or nearly fully
ionized at physiological pH

 Those that are NOT protein bound

 However, most pharmacologically active
molecules tend to be:
 Lipohilic
 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
 Example - Pentobarbital
 Highly lipophilic anesthetic agent
 Would exert its pharmacological effect
for 100 years if it weren’t for drug
metabolism.
 In general, most drugs are metabolized
into molecules that are more water soluble
 Usually, drug metabolites are less active
pharmacologically than the parent
compound.

the rate of drug metabolism is

the primary determinant of both duration
and intensity of drug action
 Drug Metabolism
 Most metabolism occurs in the liver
 Certain other organs and tissues can
metabolize substances
 GI mucosa
 Lower bowel – microorganisms may play
a major role
 kidneys  skin

 lung  Others – e.g. nasal mucosa

 Drug Metabolism
 Enzyme involved are distinct from those
that breakdown foodstuffs.
 Drugs absorbed from the GI tract are
first transported to the liver via the portal
vein.
 When drugs are extensively metabolized
during the initial pass through the liver, it is
called first pass effect.
 Many drug metabolizing enzymes are
located in the endoplasmic reticulum of
the liver and other tissues.
 Drug metabolism reactions are divided
into two main categories:

 Phase I
 Phase II
 Drug Metabolism: Phase I

 Converts drug to a more polar compound

by unmasking or inserting a functional
group (eg. oxidation, reduction, hydrolysis)

Metabolites may still NOT be sufficiently

water soluble for renal excretion. Many undergo
phase II reactions to increase water solubility
even further.
 Phase I Reactions
 Performed by the mixed function oxidases
or cytochrome P450 system
 Present in the smooth endoplasmic
reticulum of liver cells

Major P-450 Isoforms

 CYP1A2, CYP2A6, CYP2C6, CYP2C9
 CYP3A4 – responsible for more than
60% of drugs metabolized by the liver
  N-Dealkylation

RNHCH3 RNH2 + CH2O

Examples : Imipramine, diazepam, codeine,

erythromycin, morphine, tamoxifen,
theophylline
 Drug Metabolism: Phase II
 Increase polar nature of the compound
by adding an endogenous substance
Example: conjugation with glucuronic
acid or sulfate
 Some of the conjugation products may
undergo a phase I reaction.
 Synthetic reactions – couples drug with
an endogenous substance
III. Conjugation Reactions
 Glucuronidation
COOH
COOH
O R
OH + UDP
+R OH
OH
O OH
OH OH
OH UDP
UDP-glucuronide acid

Examples : Acetaminophen, morphine

 Endogenous substances

 Glucorinic acid

 Sulfate

 Glycine

 Acetate

 This often occurs to substances that have

undergone phase I metabolism
 Phase 1 Phase 2
Drug Derivative Conjugate

OH
Hydroxylation Conjugation OH
HO

COOH COOH COOH

O COOH
OCOCH3 OH

Aspirin Salicilylic acid Glucuronide

 Example of the whole system
 benzene – very lipid soluble
 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
 Induction of Metabolism
 Inducers enhance the rate of P450
synthesis and / or reduce its degradation.
 Various isoenzymes may be induced
selectively
 induced forms may differ from original
 many therapeutic agents induce
metabolism
 many environmental substances also
induce metabolism
 Inhibition
 Certain substances inhibit cytochrome
P450 activity
 Some substances such as certain
macrolide antibiotics (e.g. erythromycin)
irreversibly inhibit the P450 reactions
 Imidazoles such as cimetidine, or
ketoconazole bind to cytochrome oxidase
and therefore inhibit metabolism
competitively