A Textbook of Clinical Pharmacology and Therapeutics

(dopamine, noradrenaline and adrenaline), tyramine, phenyl-

ephrine and tryptophan derivatives (5-hydroxytryptamine

and tryptamine). Oxidation of purines by xanthine oxidase

(e.g. 6-mercaptopurine is inactivated to 6-thiouric acid) is

non-microsomal.

REDUCTION

This includes, for example, enzymic reduction of double

bonds, e.g. methadone,naloxone.

HYDROLYSIS

Esterases catalyse hydrolytic conversions of many drugs.

Examples include the cleavage of suxamethonium by plasma

cholinesterase, an enzyme that exhibits pharmacogenetic varia-

tion (Chapter 14), as well as hydrolysis of aspirin(acetylsalicylic

acid) to salicylate, and the hydrolysis of enalapriltoenalaprilat.

PHASE II METABOLISM (TRANSFERASE

REACTIONS)

AMINO ACID REACTIONS

Glycine and glutamine are the amino acids chiefly involved in

conjugation reactions in humans. Glycine forms conjugates

with nicotinic acid and salicylate, whilst glutamine forms con-

jugates with p-aminosalicylate. Hepatocellular damage depletes

the intracellular pool of these amino acids, thus restricting this

pathway. Amino acid conjugation is reduced in neonates

(Chapter 10).

ACETYLATION

Acetate derived from acetyl coenzyme A conjugates with several

drugs, including isoniazid,hydralazineandprocainamide(see

Chapter 14 for pharmacogenetics of acetylation). Acetylating

activity resides in the cytosol and occurs in leucocytes, gastro-

intestinal epithelium and the liver (in reticulo-endothelial rather

than parenchymal cells).

GLUCURONIDATION

Conjugation reactions between glucuronic acid and carboxyl

groups are involved in the metabolism of bilirubin, salicylates

and thromboxanes are CYP450 enzymes with distinct
specificities.

REDUCTION

Reduction requires reduced NADP-cytochrome-c reductase or
reduced NAD-cytochrome b5 reductase.

HYDROLYSIS

Pethidine(meperidine) is de-esterified to meperidinic acid by
hepatic membrane-bound esterase activity.

NON-ENDOPLASMIC RETICULUM DRUG

METABOLISM

OXIDATION

Oxidation of ethanol to acetaldehyde and of chloral to
trichlorethanol is catalysed by a cytosolic enzyme (alcohol
dehydrogenase) whose substrates also include vitamin A.
Monoamine oxidase (MAO) is a membrane-bound mitochon-
drial enzyme that oxidatively deaminates primary amines to
aldehydes (which are further oxidized to carboxylic acids) or
ketones. Monoamine oxidase is found in liver, kidney, intestine
and nervous tissue, and its substrates include catecholamines

PHASEII METABOLISM(TRANSFERASEREACTIONS) 25

DRUG

Phase I

(predominantly

CYP450)

Phase II

(transferase

reactions)

• Oxidation


• Reduction


• Hydrolysis
  
  
  • Acetylation
  
  
  • Methylation
  
  
  • Glucuronidation
  
  
  • Sulphation
  
  
  • Mercaptopuric
    acid formation
  
  
  • Glutathione
    conjugation
  
  
  
  

Renal (or biliary)

(a) excretion

O

OO

NH

H

N

HO

O

OO

NH

H

N

OH O

OH

OH

CO 2 H

O

O

O

O

NH

H

N

Phase I Phase II

Phenobarbital p-Hydroxy

phenobarbital

p-Hydroxy phenobarbital
glucuronide
(b)
Figure 5.1:(a) Phases I and II of drug metabolism. (b) A specific example of phases I and II of drug metabolism, in the case of
phenobarbital.