1. Methylation
Methylation with methyl group transfer from S-adenosyl methionine, although feasible, is not an important pathway for drug metabolism.
Methylation is an important reaction in the biosynthesis of endogenous compounds.
Methylation is an important reaction in the inactivation of biogenic amines such as catecholamines .

2. Methylation reactions
Transfer of a methyl group from the cofactor S-adenosylmethionine (SAM) to the substrate by means of a methltransferase.
Methyl group in S-adenosylmethionine is bound to a solfonium center, giving it a marked electrophilic character.

4. The natural catecholamines on the other hand, are methylated on the phenolic OH groups in the presence of catechol-O-methyl transferase (COMT)

5. The metabolism of foreign compounds
Methyltransferases …….
Catechol-O-methyltransferase
Phenol-O-methyltransferase
Non-specific N-methyltransferase and S-methyltransferase.

8. PHASE II Reactions Glucuronide conjugation Sulphate conjugation
Acetylation and Acylation
Glycine conjugation
Glutathion and mercapturic acid synthesis
Methylation reactions

9. Conjugation reactions are characterized by the following criteria
They are catalyzed by enzymes known as transferases.
They involve cofactor.
The endogenous moiety is highly polar except for methylation and ethylation.

10. Glucuronide Conjugation

11. Glucuronidation is the most common pathway in the drug metabolism for several reasons
A readily available supply of D-glucuronic acid (D-glucose).
Numerous functional groups that can combine enzymatically with glucuronic acid
The glucuronyl moiety increase the water solubility of the conjugated product.

12. The mechanism of glucuronidation
Nucleophilic substitution with inversion of configuration, α-D-glucuronic acid in UDPGA forming β-D-glucuronides.
The functional groups able to undergo glucuronidation are classified as O-, N-, S- and C- glucuronides.

13. Sulphate conjugation

16. Conjugation Reactions Acetylation

18. Amino acid conjugation

19. Glutathion and mercapturic acid synthesis

23. Overview - METABOLISM … metabolism is what the body does to the drug
Drug molecules are processed by enzymes evolved to cope with natural compounds
Drug may have actions increased or decreased or changed
Individual variation genetically determined
May be several routes of metabolism
May not be what terminates drug action
May take place anywhere BUT liver is prime site
Not constant - can be changed by other drugs; basic of many drug-drug interactions
… metabolism is what the body does to the drug