1. Pharmacokinetics: Metabolism of Drugs
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture-8
February 26, 2012

2. Pharmacokinetic Components

3. Drug Metabolism
Drug metabolism is a process by which drugs are inactivated by living organisms, usually through specialized enzymatic systems
Metabolism often converts lipophilic drugs into more readily excreted polar products
Not all metabolic processes result in inactivation and drug activity is sometimes increased by metabolism
Liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues

4. Kinetics of Metabolism
Two types of receptor kinetics:
First-order kinetics
Zero-order kinetics
First-order Kinetics
A constant fraction of the drug in the body is eliminated per unit time
The rate of elimination is proportional to the amount of drug in the body
The majority of drugs are eliminated in this way

5. First-order elimination
5 units/h
Elimination rate 8
Plasma concentration
2.5 units/h 4 2
1.25 units/h 1
Time (h)

6. Zero-order Kinetics
A constant amount of drug is eliminated per unit time
This form of kinetics occur with several important drugs at high dosage concentrations, e.g., phenytoin, ethanol, theophylline
Under this condition metabolizing enzymes are saturated by high free-drug concentration

7. Zero-order elimination
2.5 units/h
Elimination time
Plasma concentration
2.5 units/h
2.5 units/h
Time (h)

8. Reactions of Drug Metabolism
The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal tubules
Therefore, lipid-soluble agents must first be metabolized in the liver using two general sets of reactions
Phase 1 reaction
Phase 2 reaction

9. Phase 1 Reaction
Convert lipophilic molecules into polar molecules by introducing a polar functional group, such as -OH or -NH2
If the metabolites of phase 1 reactions are sufficiently polar, they may be readily excreted at this point
CYP450 system is important for the metabolism and biotransformation of exogenous substances (drugs)
Reaction can be fulfilled by amine oxidation (catecholamines), alcohol dehydrogenation (ethanol oxidation), and hydrolysis

10. Phase 2 Reaction It is a conjugation reaction
If the metabolites of phase 1 reactions are not sufficiently polar, they undergo a subsequent conjugation reaction with endogenous substance, such as glucoronic acid, sulfuric acid, acetic acid, or an amino acid
These conjugates are polar, and most often inactive
Highly polar drug conjugates may then be excreted by the kidney
Sites on drugs where conjugation reactions occur include -COOH, -OH, or NH2 groups,

11. Phase1 Vs Phase 2 Reaction
Drug
Derivative
Conjugate
Oxidation
Hydroxylation
Hydrolysis
Conjugation
Example
Glucoronic acid
Salicylic acid
Glucoronide

12. Metabolism of Drugs at Intestine
Important for drugs undergoing enterohepatic circulation
Estradiol is excreted in bile as a glucoronide conjugate, loses glucoronic acid, as a result, free drug is available for reabsorption via the intestine
Net effect of enterohepatic
recirculation is that each bile
salt is reused many times
Enterohepatic Circulation

13. Presystemic Metabolism and First Pass Effects
This is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation
It is fraction of lost drug during the process of absorption which is generally related to the liver and gut wall
It reduces the bioavailability of the drug

14. Factors Affecting Metabolism
Genetic variation influenced on bioavailability
CYP450 monooxygenases systems can vary with ethnicity
Pathologic condition can influence drug metabolism, including kidney, liver or heart disease
Physiological factors such as age can influence on drug metabolism

15. Enzyme Induction
Enzyme induction is a process in which a drug induces (i.e. initiates or enhances) the expression of an enzyme
There is a rise in CYP450 content and increased CYP450 reductase activity
Size of liver and hepatic blood flow increases
If two or more drugs are given simultaneously, then one substance that is an inducing agent accelerate the metabolism of other drugs

16. Enzyme Inhibition
Enzyme inhibition can refer to the inhibition of the expression of the enzyme by another molecule
Types of enzyme inhibition:
competitive
uncompetitive
non-competitive
partially competitive