biph_t_7

Biopharmaceutic
Lec.7 Elimination of Drug
Assistant Lecturer: Hussein Jabbar

M.Sc. (UOB)
Continents
❑ Drug Metabolism
❑ Phases Of Metabolism
❑ Drug Interactions
❑ Factors Affecting Metabolism
❑ Drug Excretion
❑ Renal Excretion
❑ Fecal Excretion
❑ Pulmonary Excretion
❑ Salivary Excretion
❑ Skin Excretion
Mammillary Excretion
Drug Metabolism
Drug metabolism
• Metabolism is defined as: The irreversible biotransformation
of drug in the body → typically involves making it more polar
to enhance renal excretion.
• Drug metabolism often converts lipophilic chemical
compounds into:
➢More hydrophilic
➢Have their actions decreased (become less effective) or
increased (become more effective)
➢May be converted to less toxic or more toxic metabolites or
to metabolites with different type of effect or toxicity
• The metabolism of drugs takes place mainly in the liver (the
smooth endoplasmic reticulum of the liver cell) .
• However, other organs such as the kidney, lung, intestine and
placenta can also be involved in this process.
• Occasionally the metabolite is less water soluble.

A significant example is the acetyl metabolite of some of the
sulfonamides.
Some of the earlier sulfonamides are acetylated to relatively
insoluble metabolites which precipitated in urine, crystalluria.
Now the more commonly used sulfonamides have different
elimination and solubility properties and exhibit less
problems.
Two Types of Metabolic Reactions
Phase I reactions:
• Change drugs to more hydrophilic metabolites which are
more readily excreted
• Introduce into the drug molecule sites for phase II reactions
• May be less toxic (but not always)
• Mostly occur in the endoplasmic reticulum (microsomes) of
liver cells.
• Usually involve oxidation, reduction, hydrolysis or other
reactions
Phase I reactions:
1- Oxidation
Oxidation is the addition of oxygen and/or the removal of
hydrogen, carried out by oxidases .
• Most oxidation steps occur in the endoplasmic reticulum.
• These oxidative reactions typically involve a cytochrome
P450, NADPH and oxygen.
• Common reactions include :-
• Alkyl group ----> alcohol
Phase I reactions:
Aromatic ring ----> phenol
Oxidation at S or N
Phase I reactions:
2. Reduction
Add a hydrogen or remove oxygen
azo (-N=N-) or nitro groups (-NO2) -----> amines (-NH2)
• for example nitrazepam
3.Hydrolysis
Addition of water with breakdown of molecule.
Esters ---> alcohol and acid
for example aspirin to salicylic acid

Phase II
1. Conjugation
Conjugation reactions covalently add large, polar endogenous molecules to
parent drug or Phase I metabolite →inactive and excretable (glucuronide,
glutathione, sulfate, acetate, amino acids etc)
A- Glucuronidation
This is the main conjugation reaction in the body.
This occurs in the liver.
Aliphatic alcohols and phenols are commonly conjugated with glucuronide.
Thus hydroxylated metabolites can also be conjugated.
For example morphine.
Phase II
B- Acylation
Acylation, especially acetylation with the acetyl group, e.g.
sulfonamides.
C- Glycine
Glycine addition (NH2CH2COOH) for example nicotinic acid
D- Sulfate
Sulfate (-SO4) for example morphine, paracetamol
• In most cases the metabolites are inactive, however,
occasionally the metabolite is also active, even to the extent
that the metabolite may be the preferred compound to be
administered. The original drug may take on the role of a
pro-drug. For example:
codeine ------> morphine

primidone ---> phenobarbital
Drug Interactions
• Drug metabolism can be quantitatively altered by drug interactions. This alteration
can be an increase by induction of enzyme activity or a reduction by competitive
inhibition.
I. Induction
• Induction ~ ↑ metabolic activity of enzyme = ↓ [drug]
E.g. Phenobarbitone will induce the metabolism of itself, phenytoin, warfarin, etc.
E.g. Cigarette smoking can cause increased elimination of theophylline.
E.g. alcohol
• Dosing rates may need to be increased to maintain effective plasma
concentrations.
Drug Interactions
II. Inhibition
Inhibition ~ ↓ metabolic activity of enzyme = ↑ [drug]
E.g. grapefruit juice.
E.g. Warfarin inhibits tolbutamide elimination which can lead
to the accumulation of drug and may require a downward
adjustment of dose.
E.g. Cimetidine is a therapeutic agent (prevent ulcer) that has
been found to impair the in vivo metabolism of other drugs.
Factors that can influence drug metabolism:
1. Age:
Drugs metabolism is slower in fetal, neonatal and elderly humans
than in adults.
2. Sex:
women metabolize alcohol more slowly than men
3. Other drugs:
Certain drugs (enzyme inducers) can increase the rate of
metabolism of active drugs (enzyme induction) and thus decrease
the duration and intensity of the their action. The opposite is also
true (enzyme inhibition)
Factors that can influence drug metabolism:
4. Food:
Grapefruit juice contains furanocoumarins which inhibit drug
metabolism by interfering with hepatic cytochrome P450.
5. Genetic variation (polymorphism):
With Nacetyltransferases (involved in Phase II reactions), individual
variation creates a group of people who acetylate drugs (isoniazid)
slowly (slow acetylators) and those who acetylate quickly.
This variation may have dramatic consequences, as the slow acetylators
are more prone to dose dependent toxicity.
13% of Egyptians are slow acetylators. Warfarin (bleeding) and
phenytoin (ataxia) are examples
Factors That Can Influence Drug Metabolism:
6. Physiological factors
That can influence drug metabolism include age,individual
variation (e.g., pharmacogenetics), enterohepatic circulation,
nutrition, intestinal flora, or sex differences.
7. Pathological factors
Can also influence drug metabolism, including liver, kidney, or
heart diseases.
Diseases and Drug Metabolism:
1-Liver Disease:
• Acute or chronic diseases that affect liver function markedly affect hepatic
metabolism of some drugs.
• Such conditions include fat accumulation, alcoholic cirrhosis, biliary
cirrhosis, and acute viral or drug hepatitis.
• These conditions may impair hepatic drug metabolizing enzymes,
particularly microsomal oxidases, and thereby markedly affect drug
elimination.
• For example, the half-life of diazepam in patients with liver cirrhosis or
acute viral hepatitis is greatly increased, with a corresponding prolongation
of its effect.
2-Cardiac Disease:
• Cardiac disease, by limiting blood flow to the liver, may impair disposition
of those drugs whose metabolism is flow-limited.
Drug Excretion
Drug excretion:
Drug excretion:
1. Renal excretion:
The major organ for the excretion of drugs is the KIDNEY.
• The functional unit of the kidney is the nephron in which

there are three major processes to consider:
1) Passive glomerular filtration
2) Active tubular secretion
3) Passive tubular re-absorption
1) Glomerular filtration
2) Tubular secretion
3)Tubular re-absorption
Renal Clearance:
• One method of quantitatively describing the renal excretion of
drugs is by means of the renal clearance value for the drug.
• Renal clearance can be used to investigate the mechanism of drug
excretion:
• A- If the drug is filtered but not secreted or reabsorbed the renal
clearance will be about 120 ml/min in normal subjects.
• B- If the renal clearance is less than 120 ml/min then we can assume
that at least two processes are in operation, glomerular filtration and
tubular re-absorption.
• C- If the renal clearance is greater than 120 ml/min then tubular
secretion must be contributing to the elimination process.
Factors Altering Renal Drug Clearance:
• Renal drug clearance is lower [therefore you must reduce
dose] in:
1. Elderly and Newborn

2. Women (20%) than men
3. Kidney and Heart Disease
4. Patients taking drugs which block secretion (aspirin,
probenecid)
Hemodialysis:
• Hemodialysis or `artificial kidney' therapy is used in renal
failure to remove toxic waste material normally removed by
the kidneys.
• In the procedure blood is diverted externally and allowed to
flow across a semi-permeable membrane that is bathed with
an aqueous isotonic solution.
• Nitrogenous waste products and some drugs will diffuse
from the blood, thus these compounds will be eliminated.
Hemodialysis:
• This technique is particularly important with drugs which:-
1) have good water solubility.
2) Are not tightly bound to plasma protein.
3) Are smaller molecular weight.
4) Have a small apparent volume of distribution.
Drugs which are tightly bound or extensively stored or

distributed into tissues are poorly removed by this process.
2- Fecal excretion:
• Elimination of toxicants in the feces occurs from two processes:
A- Excretion in bile:
Some heavy metals are excreted in the bile, e.g., arsenic, lead, and mercury.
However, the most likely substances to be excreted via the bile are
comparatively large, ionized molecules, such as large molecular weight
(greater than 300) conjugates e.g. morphine and chloramphenicol (as
glucuronide). –
The biliary secretion is active since bile/plasma concentrations may be as
high as 50/1.
There can also be competition between compounds.
2-Fecal excretion:
• Once a substance has been excreted by the liver into the bile, and
subsequently into the intestinal tract, it can then be eliminated from
the body in the feces, or it may be reabsorbed.
• Since most of the substances excreted in the bile are water-soluble,
they are not likely to be reabsorbed as such.
• However, enzymes in the intestinal flora are capable of hydrolyzing
some glucuronide and sulfate conjugates, which can release the less-
polar compounds that may then be reabsorbed. This process is
known as the enterohepatic circulation.
• The effect of this enterohepatic circulation is to prolong the life of the
drug in the body.
• Another way that drugs can be eliminated via the feces is by:
B- Direct intestinal excretion:

• Orally administered drugs may be excreted in the feces if
they are incompletely absorbed or not absorbed at all (e.g.
Cholestyramine)
• Increasing the lipid content of the intestinal tract can
enhance intestinal excretion of some lipophilic substances.
For this reason, mineral oil is sometimes added to the diet to
help eliminate toxic substances, which are known to be
excreted directly into the intestinal tract.
• Drugs may be excreted by passive diffusion from:
3. Pulmonary excretion:
• The lung is the major organ of excretion for gaseous and
volatile substances.
• Most of the gaseous anesthetics are extensively eliminated
in expired air.
4. Skin excretion:
Iodine, bromine, benzoic acid, salicylic acid, lead, arsenic
mercury , iron and alcohol are examples of compounds that
excreted in sweat
5. Salivary excretion:
• Drug excretion into saliva appears to be dependent on pH partition
and protein binding.
• In some instances, salivary secretion is responsible for localized side
effects.
• For example, excretion of antibiotics may cause black hairy tongue,
and gingival hyperplasia can be a side effect of phenytoin.
6. Mammary excretion:
• Both A-basic substances and B-lipid-soluble compounds can
be excreted into milk.
• Basic substances can be concentrated in milk since milk is
more acidic (pH ~ 6.5) than blood plasma.
• Since milk contains 3-4% lipids, lipid-soluble drugs can
diffuse along with fats from plasma into the mammary gland
and thus can be present in mother's milk.
C-Substances that are chemically similar to calcium can also be
excreted into milk along with calcium.
D- Ethanol and tetracycline enter the milk by diffusion through
membrane pores (of mammary alveolar cells).
Any Question
Many Thanks

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Biopharmaceutic

Lec.7 Elimination of Drug

Assistant Lecturer: Hussein Jabbar

• Occasionally the metabolite is less water soluble.

for example aspirin to salicylic acid

codeine ------> morphine

• The functional unit of the kidney is the nephron in which

1. Elderly and Newborn

Drugs which are tightly bound or extensively stored or

B- Direct intestinal excretion:

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