Clinical Pharmacology and Therapeutics

PHASE II METABOLISM (TRANSFERASE REACTIONS) 25
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 mitochondrial
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
DRUG
(dopamine, noradrenaline and adrenaline), tyramine, phenylephrine
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 variation
(Chapter 14), as well as hydrolysis of aspirin (acetylsalicylic
acid) to salicylate, and the hydrolysis of enalapril to enalaprilat.
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 conjugates
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).
Phase I
(predominantly
CYP450)
– Oxidation
– Reduction
– Hydrolysis
Phase II
(transferase
reactions)
– Acetylation
– Methylation
– Glucuronidation
– Sulphation
– Mercaptopuric
acid formation
– Glutathione
conjugation
ACETYLATION
Acetate derived from acetyl coenzyme Aconjugates with several
drugs, including isoniazid, hydralazine and procainamide (see
Chapter 14 for pharmacogenetics of acetylation). Acetylating
activity resides in the cytosol and occurs in leucocytes, gastrointestinal
epithelium and the liver (in reticulo-endothelial rather
than parenchymal cells).
GLUCURONIDATION
(a)
Renal (or biliary)
excretion
Conjugation reactions between glucuronic acid and carboxyl
groups are involved in the metabolism of bilirubin, salicylates
O
H
N
NH
O
Phase I
HO
O
H
N
NH
O
Phase II
CO 2 H
O
OH
O
O
H
N
NH
O
O
O
OH
OH
O
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.