Lecture 16 Biotransformation I

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11 Apr 2012
Drug metabolizing enzymes are like the immune system
Can protect the host organisms from foreign substances
oDME: small molecules
oImmune system: large substances (viruses, bacteria)
Can harm host organism if not properly regulated and balanced
Drug Biotransformation stable or reactive
1. Produce stable metabolites
a. Lower PK activity (inactivation)
b. Increase PK activity (prodrug activation)
c. Retention of pharmacological activity
2. Produce reactive metabolites
Covalent binding to cellular macromolecules. Toxic consequences: cell injury or
death, carcinogenicity, teratogenicity
Reactive metabolites – undesirable, electrophillic
Inactivation example
Acetaminophen is active, but when metabolized by SULT or UGT, becomes inactive.
SULT transfers sulfer group from PAPS to acetaminophen.
UGT transfers glucronic acid
Inactive: Decreased Potency, More H20 soluble; side groups S, G governs duration of
effect in body
Activation example
Allopurinol is a weak prodrug. With the action of xanthine oxidase, it is biotransformed to
oxypurinol, an active metabolite with increased potency and half life.
Retention of activity
Procaamide is biotransformed to N-acetylprocanimide via NAT. Metabolite has
DECREASED H2) solubility (contrary to what normally happens), and increased half life.
Both are anti-arrhythmic drugs, both are active, have slightly different target selectivity,
both potent. The addition of acetate DECREASES water solubility.
Produce Reactive metabolites
Anticonvulsant drugs with aromatic rings (treat epilepsy)
Drug-macromolecule complex foreign to body autoimmune response
rejection by own skin/;over
Arene oxide unstable
Aflatoxin B1 is a procarcinogen transformed to aflatoxin B-2,3-epoxide via CYP1A2,
CYP3A4. DNA alkylation mutations cancer (binds covalently to DNA)
Increased activity AND reactivity
Nitrogen mustards metabolized by CYP3A4/2B6 aziridnium species kills cancer
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