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CLINICAL TOXICOLOGY
FEBRUARY 2014
A BRIEF REVIEW OF OPIOID METABOLISM
Several opioids go through similar metabolic processes
upon entering the human body (see the diagram). In
the human liver, the opioids can be metabolized either
by CYP3A4 to form N-demethylation metabolites, or
by CYP2D6 to form O-demethylation metabolites. All
N-demethylation metabolites are inactive metabolites
and will not affect the efficacy of the parent
medications; while all O-demethylation metabolites
possess greater analgesic potency than the parent
compounds and arguably determine the efficacy of
the parent medications. Drug metabolism proceeds
unevenly towards these two metabolic pathways.
Generally speaking, CYP3A4-mediated metabolism is
the major metabolic pathway and its metabolites
account for up to 50% of a given dose- the reason is
that CYP3A4 is the most abundant metabolic enzyme
in the human liver. The metabolites formed through
the CYP2D6 pathway usually account for 20-30% of
the dose. Elimination and metabolism of the drugs
always occur simultaneously. For hydrocodone and
oxycodone, a significant portion of an oral dose is
unchanged when eliminated in urine. Unless it is at the
very beginning or end of a dosing phase, urinary
profiles of the drugs would always consist of: the
parent compound, N-methylation metabolites, Omethylation metabolites, and other further brokendown metabolites. From previous studies [1], urinary
profiles for hydrocodone after a single dose at 72
hours were: unchanged drug (12%), norhydrocodone
(5%), hydromorphone (4%), and others (3.1%). The
urinary profiles for oxycodone after a single dose at 48
hours were: unchanged drug (8%), noroxycodone
(23%), oxymorphone (11%), and others (31.1%). The
purpose of drug monitoring is to provide information
about a patient’s status of drug compliance. Some
compounds like carisoprodol (SOMA) or clonazepam
have a very short half-life and detection window (less
than 1 day) in urine.
1. Baselt, RC. Disposition of toxic drugs and chemicals in man: 9th ed.
(2011), 812-813 and 1259-1261.
Therefore, monitoring compliance of these drugs must
exclusively depend on their metabolites in urine, since
the metabolites usually have a longer half-life and
detection window. For hydrocodone and oxycodone,
monitoring compliance can be sufficiently achieved by
measuring parent compounds, O-methylation
metabolites, and/or N-methylation metabolites. The
reasons: 1. The parent compounds themselves can
remain detectable for 1-2 days in urine. If a patient
adheres to his/her dosing regimen (every 4-6 hours
for normal-release formulations or every 12 hours for
extended-release versions), the chances of detecting
the parent compounds are already high; 2. Odemethylation metabolites (hydromorphone and
oxymorphone), just like N-demethylation metabolites
(norhydrocodone and noroxycodone), can stay in the
body longer than parent medications. This means in
case that all parent compounds are metabolized;
physicians can look for the formation of
hydromorphone or oxymorphone as an indicator of
drug compliance; 3. From a clinical point of view, Odemethylation metabolites may be more relevant
since they are pharmacologically more active than the
parent compounds.
PARENT COMPOUNDS:
N-demethylation
CYP3A4
Hydrocodone
Oxycodone
Tramadol
Codeine
O-demethylation
CYP2D6
N-DEMETHYLATION
PRODUCTS:
O-DEMETHYLATION
PRODUCTS:
Norcodeine
Noroxycodone
Norhydrocodone
N-desmethyltramadol
Morphine
Oxymorphone
Hydromorphone
O-desmethyltramadol
Urine and Oral Fluid Confirmatory Drug Testing Laboratory - Support pain management - Monitor compliance - Identify undisclosed medications
Cheng Fang, MD., PH D., DABT | [email protected]
721 Cortaro Dr, Sun City Center, FL 33573 | T 866-762-8379 | F 813-634-4538