Pharmacokinetics II

MBBS-Y1, Sem2, 2020

Prof. Dr Abdelbaset Taher 1

• Learning Objectives
− Define biotransformation of drugs
− Classify biotransformation reaction
− Explain sites of biotransformation
− Discuss effect of drugs on hepatic
microsomal enzymes
− Enumerate channels of drug excretion
− Discuss processes of renal excretion
Prof. Dr Abdelbaset Taher 2
 III. Biotransformation

• Definition:
− The chemical alterations which a drug
undergoes within a living organism
• Aiming
– To convert lipid soluble drugs into more polar
compounds with hydrophilic properties, thus
facilitating their renal excretion.
• Resulting
– Usually: loss of activity of the parent drug,
rarely activation may occur.
* Prof. Dr Abdelbaset Taher 3
Classification of biotransformation reactions:
• Phase I (non synthetic reactions)

1. Oxidation
= e.g. ethyl alcohol  acetaldehyde  acetic acid
 CO2 + H2O + E
2. Reduction
= e.g. chloral hydrate  trichloroethanol
3. Hydrolysis
= e.g. acetyl choline  choline + acetic acid

Prof. Dr Abdelbaset Taher

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non synthetic reactions may result in:
1. Conversion of inactive compound to active one i.e.
activation.
Imipramine ─(oxid)→ desipramine
(inactive) (active)

2. Conversion of an active drug to a metabolite that is

also active
Phenacetin ─(oxid)→ acetaminophen
(active) (more active)
N.B. acetaminophen= paracetamol

3. Inactivation
Acetyl choline ─(hydrolysis)→ choline + acetic acid
4. Conversion to a toxic compound
methanol ─(oxid)→ formaldehyde
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(retinotoxic)
Phase II (synthetic reactions):
– They involve conjugation of the parent
compound or its metabolite with certain acid
radicals or amino acids.
– They always result in inactivation of the parent
drug. The conjugated product is more H2O
soluble.
Examples of synthetic reactions:
– Conjugation of chloramphenicol with glucuronic acid.
– Conjugation of sulphonamides with acetic acid.
– Conjugation of salicylate (aspirin) with glycine.

Prof. Dr Abdelbaset Taher 6

 Sites of biotransformation

Hepatic microsomal enzymes Non microsomal biotransf.

(P-450)

Sites Liver (endoplasmic reticulum). Liver, other tissues, digestive

juices, plasma, bact. flora

Role Glucuronide conj. + most Conjugation (other than

oxidative reactions gluco… + some oxidative

Reduction and hydrolysis Reduction and hydrolysis

Activity - ↑ by activator drugs, growth &

development
- ↓ by inhibitor drugs, neonate, Not affected by drugs
old age, starvation, cancer, liver
dis.
‫ا‬Must be Lipid solubility
Prof. Dr Abel Baset Taher Not necessary 7
Effect of drugs on hepatic microsomal enzymes:
a) Activators:
− many drugs are capable of enhancing the activity of these
enzymes  ↑ ability of detoxication (such drugs ↑ their own
rate of degradation as well as the rate of degradation of
concomitantly administered drugs e.g. phenobarbitone,
phenytoin, imipramine….
− This type of enzyme activation is described as enzyme
induction.
b) Inhibitors:
− certain drugs can inhibit the activity of microsomal enzymes
and may delay the rate of degradation of other drugs thus
enhancing and prolonging their effects.
− e.g. chloramphenicol, cimetidine, clofibrate …….., hormones
(estrogen and progesterone).
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Diseases affecting drug metabolism:
1. Liver diseases (cancer, acute, chronic)
↓ activity of enzymes (microsomal)  ↑ activity of many
drugs e.g. aminopyrine, diazepam and even May  coma.
2. Cardiac disease
 ↓ blood supply to liver  affect metabolism.
3. Pulmonary disease or cancer
 ↓ metabolism of procainamide, antipyrine.
4. Endocrine diseases
─(thyroid)→ affect metabolism of antipyrine, digitalis ….
5. Kidney diseases
 phenobarbitone is used with caution in renal failure as it
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depends on renal clearance for excretion.
 IX. Excretion

• Drugs in the free form and in the form of

their degradation products are eliminated
through one or more of the following
channels.
a) Kidneys:
these excrete all non-volatile drugs and their
degradation products as well as some volatile
drugs.

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With regards to renal excretion, it's important to
note that:
− Strongly protein-bound
drugs are only slowly filtered by glomeruli e.g. short acting
barbiturates.
− Non metabolized drugs are excreted unchanged in
the urine.
E.g. Acetazolamide and frusemide are excreted unchanged
– The urinary PH:
the higher PH favors the excretion of acidic drugs e.g.
Aspirin, while a lower PH favors excretion of basic drugs e.g. ephedrine.

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Renal excretion occurs through 3 different processes:
1. Glomerular filtration:
the drug must be free and water soluble
2. Active secretion:
− occurs in the proximal tubules by 2 active transport systems
requiring a carrier:
..For organic acids e.g. penicillin
..For organic bases e.g. amphetamine

− These transport systems show low specificity and

competition between drugs for the carrier e.g. probenecid
competes with penicillin tubular secretion of penicillin
and plasma level.
3. Passive reabsorption:
− concentration of the drug  as it moves towards the distal
tubules, if it is lipid soluble and unionized reabsorption
occurs. 12
b) Lungs:
– The lungs excrete gaseous and volatile general
anesthetics as well as gaseous drug products
e.g. CO2.

c) Skin glands:
– The sweat and mammary glands excrete drugs
to a limited extent. Excretion through milk is
important in lactating mothers, while excretion in
sweat may lead to skin disorders.

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d) Alimentary tract:
• Salivary glands:
− excretion through saliva is limited
− e.g. iodides.
• Stomach:
− very few drugs are excreted by stomach
− e.g. morphine.
• Bile:
− some drugs may be excreted in bile. However
reabsorption may occur from intestine (enterohepatic
circulation)  prolongation of action of drugs
− e.g. phenolphthalein.
• Colon:
− excrete unabsorbable residue e.g. iron + the part 14
excreted by upper part of GIT.
 Thank you

Prof. Dr Abdelbaset Taher 15