Drug metabolism

[Ref: SH4:p14]

Role of metabolism

.. to convert lipid-soluble drug into water-soluble metabolites

By increasing water solubility
--> Decrease Vd, and enhance renal excretion and sometimes GIT elimination

 

Metabolism does not always lead to pharmacologically inactive metabolite

e.g. diazepam and propranolol may be metabolised into active compounds

 

Rate of metabolism

Rate of metabolism depends on

• Concentration of drug at the site of metabolism
• Intrinsic rate of metabolism process

First-order kinetics

Amount of drug eliminated is proportional to the plasma concentration

e.g. Most drugs

Zero-order kinetics

Constant amount of drug is eliminated, regardless of plasma concentration
* Occurs when the plasma concentration exceeds enzyme capacity

e.g. alcohol, aspirin, phenytoin

 

Pathways of metabolism

4 basic pathways

1. Oxidation
   * e.g. hydroxylation, deamination, desulfuration, dealkylation, dehalogenation
   * Reactive intermediates may cause organ damage
2. Reduction
   * More common when oxygen partial pressure is low
3. Hydrolysis
   * Do not involve cytochrome P-450 enzymes
   * Nonmicrosomal enzymes are involved
4. Conjugation
   * Conjugation with glucuronic acid involves cytochrome P-450 enzymes
   * Decreased in neonates and during pregnancy

2 phases

1. Phase I
   * Oxidation, reduction, and hydrolysis
   * Increase drug's polarity, preparing it for phase II
2. Phase II
   * Conjugation reactions
   * Increase water solubility by linking with a highly polar molecule

Site of metabolism

• Liver
• Plasma (Hofmann elimination, ester hydrolysis)
• Lungs
• Kidneys
• GIT
  * Especially small intestine
  * Cytochrome P-450 enzymes

Enzymes involved

Microsomal enzymes
* Mainly located in the hepatic smooth endoplasmic reticulum
* Can also be present in kidney, GIT, adrenal cortex