Pharmacokinetics

• What the body does to the drug – movement and reaction

• ADME!
What is Drug Metabolism ?
• Biochemical changes that involve the modification of a drug by
endogenous metabolic enzymes

Where does it take place?

• Liver (main) , kidney, lungs, gastrointestinal tract and skin

Effects on Drugs?
• Inactivate a drug – Naproxen (pain killer) > Inactive metabolites

• Activate a drug (prodrug) – Levodopa > Dopamine (Parkinson’s Disease treatment)

• Mild effects on bioactivity as both drug and its metabolites are active – Digitoxin > Digoxin (heart disease treatment)
 Metabolism
Phase I Phase II
• Increase the hydrophilicity of a lipophilic drug – • Further increase water solubility of hydrophilic
drugs/metabolites by conjugation with highly polar moiety
➢ Inserts hydrophilic functional groups into the chemical (slightly soluble to very soluble)
structure of admistarted drug

➢ Convert lipophilic functional groups to hydrophilic functional

group
• Ultimate goal : slightly soluble drugs/metabolites to water
soluble metabolites (excretion)
• Reactions involved : Acetylation, glucuronidation, glutathione
conjugation, sulfation
➢ Ultimate goal : Insoluble drugs > slightly soluble • Enzymes involved : Glucuronosyl-, Sulfo-, Methyl-, and
metabolites Glutathione-S-transferases.
• Reactions involved : Oxidation, reduction, hydrolysis
• Enzymes involved : cytochrome P450, aldehyde oxidase,
Xanthine oxidase, Flavin-Containing Monooxygenases,
Monoamine oxidase, Esterase
Phase I

OH Insertion

Oxygen
Elimination
Alkyl Elimination

Amine
Elimination Ester/amide
Dissociation

O Insertion

Phase II
Drug metabolism Summary
Is Understanding Drug Metabolism Important?
• Yes! Utilize it to improve the bioavailability of a drug (prodrug principles).
Example 1: Tamiflu (ester hydrolysis) Example 2: Enalapril (ester hydrolysis)

Example 3: Dabigatran (ester/amide hydrolysis)

Example 4: Fosphenytoin (ester hydrolysis) Example 5: Tegafur (Oxidative activation)

Is Understanding Drug Metabolism Important?
• Yes! Avoid it to prevent metabolic deactivation of a drug

• Prevent para-hydroxylation by first pass metabolism

• Improved efficacy
• Longer half life
 Is Understanding Drug Metabolism Important?
• Yes! To treat overdose of drugs

• Hepatotoxic (Hepatitis)
• Ultimately death
• Solution = Acetylcysteine
treatment (boost GSH)