Pharmacokinetic principles (metabolism and excretion)

1. Pharmacokinetic principles-2
Dr. M. Ahsan (MBBS, MD)

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

5. Drug
(lipophilic)
Oxidation,
Reduction,
And/or
Hydrolysis
(polar)
Conjugation products
(water soluble)
Phase I Phase II
Following phase I, the drug may be activated,
unchanged, or most often, inactivated
Conjugated drug is usually
inactive
Some drugs directly enter
phase II metabolism

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

7. CYP3A4
36%
CYP2D6
19%
CYP2C8/9
16%
CYP1A2
11%
CYP2C19
8%
CYP2E1
4%
CYP2B6
3%
CYP2A6
3%
Relative contribution of cytochrome 450 (CYP) isoforms to
drug biotransformation
CYP3A4 CYP2D6 CYP2C8/9 CYP1A2 CYP2C19 CYP2E1 CYP2B6 CYP2A6
Four isoenzymes
(CYPA3A4, CYP2D6,
CYP2C8/9, and
CYP1A2) are
responsible for the
majority of P450-
catalyzed reactions
CYP3A4 carries out
metabolism of largest
number of drugs

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

10. Microsomal enzymes
Microsomal enzyme inhibitors
• Allopurinol
• Erythromycin
• Ketoconazole
• Cimetidine
• HIV protease inhibitors
• Grape juice
Microsomal enzyme inducers
• Anticonvulsants, rifampin induce
CYP3A4
• Isoniazid and alcohol induce
CYP2E1
• Polycyclic hydrocarbons in
cigarette smoke, charcoal broiled
meat induce CYP1A

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

15. Kinetics of metabolism
• First-order kinetics
• Zero-order kinetics

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

25. Thank you

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.