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 .

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.

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

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

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

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.

Glucuronide Conjugation

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.

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.

Sulphate conjugation

Conjugation Reactions Acetylation

Amino acid conjugation

Glutathion and mercapturic acid synthesis

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