2. Biotransformation/ Drug metabolism
Biotransformation means chemical transformation of the drug in the body
Primary site: LIVER
Other sites: kidney, intestine, lungs and plasma
Importance:
converts non-polar (lipid soluble) compounds to polar (lipid-insoluble)
…….so that they are not reabsorbed in the renal tubules and are excreted
3. Biotransformation/ Drug metabolism
Biotransformation of drugs may lead to:
Inactivation of active drug
Active metabolite from an active drug
Activation of inactive drug
Few drugs are inactive and need conversion in the body
to one or more active metabolites.
Such a drug is called PRODRUG
4. Biotransformation
Biotransformation reactions may be classified into:
A. Phase I / Non-synthetic / Functionalization reactions
a functional group is generated or exposed
converts lipophilic drug to polar molecules
metabolite may be active or inactive
B. Phase II / Synthetic / Conjugation reactions
an endogenous radical is conjugated to the drug metabolite
metabolite is mostly inactive
6. Phase I
• Oxidation
• Reduction
• Hydrolysis
• Cyclization
• Decyclization
• Oxidation reactions are the most
common
• Mostly carried out by
monooxygenases in the liver:
cytochrome P450
• Different cytochrome P450
isoenzymes have affinity for
different substrates
8. Phase II
• Glucuronide conjugation
• Acetylation
• Methylation
• Sulfate conjugation
• Glycine conjugation
• Glutathione conjugation
• Ribonucleoside/nucleotide synthesis
Glucuronide conjugation is
the most important
synthetic reaction carried
out by UDP-glucuronosyl
transferases (UGTs)
9. Microsomal enzymes
• The monooxygenases, cytochrome P450, UGTs, etc are microsomal
enzymes they are located on the smooth endoplasmic reticulum
(in liver, kidney, intestine, etc)
• Microsomal enzymes can be induced or inhibited by drugs and diet
11. Discuss Consequences of microsomal enzyme
induction in the following scenarios
I. Active drug Inactive drug
II. Active drug Active drug
III. Inactive drug Active drug
Explain why failure of contraception occurs when Oral Contraceptive Pills (OCPs)
are prescribed along with rifampin or anticonvulsants?
12. Elimination
It is the irreversible removal of drug from the body
It involves:
Biotransformation (drug metabolism)
Excretion
Major routes of elimination:
Hepatic metabolism
Biliary elimination
Urinary excretion
Clearance (CL): the volume of blood from which the drug is cleared per unit time
CL = 0.693 x Vd / t ½
Where t ½ = elimination half-life, Vd = apparent volume of distribution
13. Renal elimination of a drug
• Most important channel of excretion for majority of drugs
• The kidney is responsible for excreting all
water soluble substances
Net renal excretion = (Glomerular filtration
+ tubular secretion) – tubular
reabsorption
14. Excretion by other routes
Drugs and their metabolites can also be excreted in:
Faeces
Most of the drug in faeces is derived from bile
Exhaled air
Gases and volatile liquids
Saliva and sweat
Milk
16. First order kinetics
• The rate of elimination is directly
proportional to drug
concentration
• Constant fraction of drug is
eliminated per unit time
• Increase in dose, increases
elimination
• With increase in dose, t1/2
remains unaltered
• Most common
17. Zero-order kinetics
• Rate of elimination is not dependent on drug concentration
• Constant amount of drug is eliminated per unit time
• Increase in dose, does not increase elimination
• With increase in dose, t1/2 increases and there is risk of toxicity
• Rare: Ethanol, high doses of phenytoin
18. Kinetics of elimination
• Kinetics of some drugs change from first-order to zero-order with
increasing dose
Phenytoin
Tolbutamide
Theophylline
Warfarin
19. Kinetics of elimination
• First order kinetics:
V = rate of reaction = Vmax [C] / Km
Km = Michaelis constant
• Zero order kinetics:
V = rate of reaction = Vmax [C] /[C]
= Vmax
20. Plasma half-life (t ½)
Time in which plasma concentration of drug is reduced by half
T ½ = ln2/k = 0.693/k
k= CL/V
T ½ = 0.693x V/CL
T ½ is directly proportional to volume of distribution and inversely
proportional to clearance
21. Plasma half-life (t ½)
• In 1 t ½ – 50% drug is eliminated
• In 2 t ½ - 75%
• In 3 t ½ - 87.5%
• In 4 t ½ - 93.75% is eliminated
• Thus, it takes 4-5 t ½ to completely eliminate the drug
22. Therapeutic drug monitoring (TDM)
• It is the measurement of plasma concentration of drugs
• It is required in special situations
23. Uses of Therapeutic drug monitoring (TDM)
Drugs with low safety margin, eg. Digoxin, anticonvulsants,
antiarrhythmics, theophylline, aminoglycoside antibiotics, lithium
If individual variations are large, eg. Antidepressants, lithium
Potentially toxic drugs used in the presence of renal failure, eg.
Aminoglycoside antibiotics, vancomycin
In case of poisoning
In case of failure of response without any apparent reason, eg.
Antimicrobials
To check patient compliance, eg. Psychopharmacological agents
24. Therapeutic drug monitoring (TDM)
• Monitoring of plasma concentration is of no value for:
Drugs whose response is easily measurable, eg. Antihypertensives
Drugs activated in the body, eg. Levodopa
Drugs with irreversible action, eg. Organophosphates
26. References
• Goodman & Gillman’s: The Pharmacological Basis of Therapeutics,
13th edition. New York: McGraw-Hill, 2018
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer.
Notas del editor
The isoenzymes are grouped into families designated by numerals (1, 2, 3,….), each having sub-families designated by capital letters (A, B, C….), while individual isoenzymes are allotted numerals (1, 2, 3…)
Drug half-life is often used as a measure of drug clearance, because, for many drugs, Vd is a constant