(3).Biotransformation(metabolism). First pass(presystemic) metabolism.

Drug metabolism (biotransformation) is the process of chemical alteration of drugs in

the body.
Principles of biotranslormation:
1. The liver is the major site of metabolism for many drugs or other xenobiotics, but other
organs, such as the lungs, kidneys, and adrenal glands, can also metabolize drugs.
2. Many lipid-soluble, weak organic acids or bases are not readily eliminated from the
body
and must be conjugated or metabolized to compounds that are more polar and less lipidsoluble before being excreted.
3. Metabolism often, but not always, results in inactivation of the compound, e.g.:
hydrolysis
Acetyicholinecholine + Acetic acid
(active)
(inactive)
4. Some drugs are activated by metabolism. These substances are called prodrugs, e.g.:
oxidation
Imipramine Desipramine
(inactive)
(active)
oxidation
Phenacetin Acetaminophen (paracetamol)
(active)
(more active)
Types of biotransformation: non-synthetic, synthetic, presynthetic.
Biochemical reactions involved in drug metabolism occur in 2 phases:
Phase 1 reactions (oxidation, reduction, hydrolysis) alter chemical reactivity and
increaseaqueous solubility. Lipophilic molecules are converted into more-polar molecules
by C introduction of, or unmasking of a polar functional group.
Phase 2 reactions (conjugation) further increase the solubility, promoting elimination.
Formation of a covalent linkage between functional groups on the parent drug and
another
substrate (glucuronate, acetic acid, glutathione, sulfate
First-pass metabolism biotransformation that occurs before the drug reaches its site of
action. It most commonly occurs in the liver. (For example, orally administered
nitroglycerin is said to have a high first-pass metabolism because 90% of it is inactivated
by the liver. Morphine is another important drug that has a high first-pass metabolism).
Oral administration of drug intestinal absorption intestinal metabolism portal
system systemic circulation
Some drugs (e.g. stilboestrol) are concentrated in the bile and excreted into the intestine
where they be reabsorbed. This enterohepatic circulation increases the persistence of a
drug in the body.
Factors affecting drug metabolism:
1. Genetics. The most important factor is genetically determined polymorphisms. The
acetylation of isoniazid (by N-acetyltransferase) and the hydrolysis of succinyicholine
(by pseudocholinesterase) are genetically controlled. Each individual has a varying
capacity to metabolize a drug through a given pathway.

2. Chemical properties of the drug Certain drugs may stimulate or inhibit the metabolism
of the other drugs
3. Route of administration. The oral route, sublingual, intramuscular, intravenous, for
example, can result in extensive hepatic metabolism of some drugs. It results in minimal
drug delivery to the systemic circulation for certain drugs (e.g., propranolol, lidocaine).
4. Diet.
5. Dosage .Toxic doses deplete enzymes needed for detoxification reactions.
6. The liver cannot detoxify drugs, such as chioramphenicol, as well in neonates as it can
in adults. Neonates have reduced hepatic metabolism and renal excretion due to relative
organ immaturity.
7. Disease. Liver disease decreases the ability to metabolize drugs, while kidney disease
hampers the excretion of drugs.
8. Social factors. Tobacco smoking, and others.
Drug excretion is the process by which a drug or metabolite is eliminated from the body.
Routes of elimination:
1. The kidney is the most important organ for excretion of drugs. Excretion of drugs and
their metabolites into the urine involves three processes:
a) Glomerular filtration (water-soluble and polar compounds);
b) Active tubular secretion (organic acids, e.g. penicillin, bases, quinine, are transported
by these system);
c) Passive tubular reabsorption.
2. The biliary tract and the feces are important routes of excretion for some drugs that
are metabolized in the liver.
3. Other routes: air, sweat, saliva, tears and breast milk (lipid-soluble and non-ionized
compounds).

Factors modifying drug excretion through kidney.

A. Factors related to drugs:
1. Ionization of drugs: unionized drugs well reabsorbed fronf tubules excretion
decreases; ionized drugs poorly reabsorbed excretion increases.

2. Concentration of drug increases excretion increases.

3. pH of drugs: for acidic drugs excretion increases in alkaline urine; for basic drugs
excretion increases in acidic urine.
4. Rate of metabolism and excretion.
B. Factors related to kidney:
1. Extent of plasma protein binding: highless excretion; less more
excretion.
2.
Glomerular filtration rate (GFR)More GFRmore excretion.
3.
Passive tubular reabsorption.
4.
Active renal tubular secretion.
5.
Active renal tubular reabsorption.
6. Impaired renal function excretion decreases.
7. Renal blood flow increases excretion increases.
FIRST PASS (PRESYSTEMIC) METABOLISM
This refers to metabolism of a drug during its passage from the site of absorption into the
systemic circulation. All orally administered drugs are exposed to drug metabolizing
enzymes in the intestinal wall and liver (where they first reach through the portal vein).
Presystemic metabolism, of limited magnitude, can also occur in the skin (transdermally
administered drug) and in lungs (for drug reaching venous blood through any route). The
extent of first pass metabolism differs for different drugs (table 2.1) and is an important
determinant of oral bioavailability.
Drugs with high first pass metabolism have the following attributes:
(a) Oral dose is considerably higher than sublingual or parenteral dose.
(b) There is marked individual variation in the oral dose due to differences in the extent
of first pass metabolism.
(c) Oral bioavailability is apparently increased in patients with severe liver disease. (d)
Oral bioavailability of a drug is increased if another drug competing with it in first pass
metabolism is given concurrently, e.g. chlorpromazine and propranolol.