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Drug Metabolism
Tables created by Robert Barkin, PharmD MBA FCP
Many opioid and other analgesic agents are subject to metabolism and elimination via a variety of hepatic enzymes. These elimination
pathways may be directly related to impaired or excessive pharmacologic responses, depending on the coadministration of other medications capable of inducing, inhibiting, or competing for access to these enzymes, creating significant drug interactions. The following tables
identify many of the important pathways involved in analgesic metabolism and may be useful references for determining drug interactions.
Opioid Analgesics
Opioid
Alfentanil
Buprenorphine
Butorphanol
Codeine
Dihydrocodeine
Fentanyl
Hydrocodone
Hydromorphone
PG Risk* Factor
C
C
C/D
C/D
B/D
C/D
C/D
C/D
Levorphanol
Meperidine
Methadone
Morphine
Nalbuphine
Oxycodone
Oxymorphone
Pentazocine
Propoxyphene
Remifentanil
B/D
C/D
C/D
C/D
B/D
B/D
C
C/D
C/D
C
Sufentanil
Tramadol
C
C
CYP Substrate
3A4
3A4
CYP Inducer
CYP Inhibitor
1A2, 2A6, 2C19
2D6
2D6
2D6, 3A4
2D6
3A4
2D6
Phase II glucuronidation conjugated 6-OH minor
metabolites
Hepatic
2B6, 2C19, 3A4
3A4, 2C9, 2C19, 2D6
Phase II, 2D6 (minor)
Hepatic
2D6
Phase II glucuronidation
Oxidation, glucuronidation
2D6
Unknown CYP450 nonspecific esterases (blood) and
tissue
3A4
2B6, 2D6, 3A4
3A4
2D6, 3A4
2D6
2D6
Other Agents with a Disease-State-Specific Analgesic Indication
Other Analgesics
Duloxetine
Gabapentin
Pregabalin
PG Risk Factor
C
C
C
Substrate
1A2, 2D6
almost not metabolized
almost not metabolized
CYP Inducer
IA2
CYP Inhibitor
1A2, 2D6
The Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Nsaids
Acetic acid derivatives
Diclofenac (plus misoprostol)
Diclofenac
Etodolac
Indomethacin
Sulindac
Tolmetin
Carboxylic acids
Aspirin (acetylsalicylic acid, ASA)
Buffered aspirin
Choline magnesium trisalicylate
Diflunisal
Enteric-coated salicylates
Salsalate
Fenamates
Enolic acids
Meclofenamate Hepatic
Mefenamic
Meloxicam
Piroxicam
Naphthylamines
Celecoxib (Sulfonamide)
Extoracoxib
Lumiracoxib
Nabumetone
Selective COX-2 inhibitors
Propionic acids
Fenoprofen
Flurbiprofen
Ibuprofen
Ketoprofen
Naproxen; Enteric
Oxaprozin
Metabolic Substrate Pathway
Cyp450 Inhibitor
Pg Category
3A4, misoprostol: rapid de-esterification to free acid
2C9, 3A4
Hepatic
2C9, 2C19
Hepatic, prodrug (sulfide to sulfone)
Conjugation inactive metabolite
2C9, 2E1, 3A
X
C
D/C
C/D
C/D
C/D
2C9, 2C19
GI mucosa, RBC, spinal fluid, blood
Esterase
Similar to above/ASA
Saturable hepatic pathway to glucuronides
Salicylate metabolism
Hepatic conjugation
C/D
C/D
C/D
C/D
C/D
C/D
Hepatic
2C9
2C9, 3A4
C/D
C/D
C/D
C/D
C/D
2C9, 3A4
3A4
2C9
Hepatic-prodrug to 6 MNA extensive 1st pass
Extensive hepatic
2C9
2C9, 2C19
Phase II, enterohepatic recirculation
1A2, 2C9
CYP Oxidation
2C9
2D6, 2C8
2C9
2C9
C/D
C/D
C/D
C/D
C/D
C/D
C/D
C/D
C/D
C/D
C/D
The Non-NSAIDs Analgesic
Acetaminophen (APAP)
1A2, 2A6, 2C9, 2D6, 2E1, 3A4
*C/D=Prolonged Use, High Dose at Term
3A4
B