CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.
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Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA
CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.
Br J Clin Pharmacol. 2004 Mar;57(3):287-97.
- PubMed ID
- 14998425 [ View in PubMed]
- Abstract
AIM: To determine the Michaelis-Menten kinetics of hydrocodone metabolism to its O- and N-demethylated products, hydromorphone and norhydrocodone, to determine the individual cytochrome p450 enzymes involved, and to predict the in vivo hepatic intrinsic clearance of hydrocodone via these pathways. METHODS: Liver microsomes from six CYP2D6 extensive metabolizers (EM) and one CYP2D6 poor metabolizer (PM) were used to determine the kinetics of hydromorphone and norhydrocodone formation. Chemical and antibody inhibitors were used to identify the cytochrome p450 isoforms catalyzing these pathways. Expressed recombinant cytochrome p450 enzymes were used to characterize further the metabolism of hydrocodone. RESULTS: Hydromorphone formation in liver microsomes from CYP2D6 EMs was dependent on a high affinity enzyme (Km = 26 microm) contributing 95%, and to a lesser degree a low affinity enzyme (Km = 3.4 mm). In contrast, only a low affinity enzyme (Km = 8.5 mm) formed this metabolite in the liver from the CYP2D6 PM, with significantly decreased hydromorphone formation compared with the livers from the EMs. Norhydrocodone was formed by a single low affinity enzyme (Km = 5.1 mm) in livers from both CYP2D6 EM and PM. Recombinant CYP2D6 and CYP3A4 formed only hydromorphone and only norhydrocodone, respectively. Hydromorphone formation was inhibited by quinidine (a selective inhibitor of CYP2D6 activity), and monoclonal antibodies specific to CYP2D6. Troleandomycin, ketoconazole (both CYP3A4 inhibitors) and monoclonal antibodies specific for CYP3A4 inhibited norhydrocodone formation. Extrapolation of in vitro to in vivo data resulted in a predicted total hepatic clearance of 227 ml x h-1 x kg-1 and 124 ml x h-1 x kg-1 for CYP2D6 EM and PM, respectively. CONCLUSIONS: The O-demethylation of hydrocodone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity cytochrome p450 enzyme. Norhydrocodone formation was attributed to CYP3A4. Comparison of recalculated published clearance data for hydrocodone, with those predicted in the present work, indicate that about 40% of the clearance of hydrocodone is via non-CYP pathways. Our data also suggest that the genetic polymorphisms of CYP2D6 may influence hydrocodone metabolism and its therapeutic efficacy.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dihydrocodeine Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Hydrocodone Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Hydrocodone Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details Details Details Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareHydrocodoneMitotane The metabolism of Hydrocodone can be increased when combined with Mitotane. HydrocodoneRifampicin The metabolism of Hydrocodone can be increased when combined with Rifampicin. HydrocodoneEnzalutamide The metabolism of Hydrocodone can be increased when combined with Enzalutamide. HydrocodoneLumacaftor The metabolism of Hydrocodone can be increased when combined with Lumacaftor. HydrocodoneApalutamide The metabolism of Hydrocodone can be increased when combined with Apalutamide.