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.2004 Mar;57(3):287-97.
doi: 10.1046/j.1365-2125.2003.02002.x.

CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes

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CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes

Mark R Hutchinson et al. Br J Clin Pharmacol.2004 Mar.

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.

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Figures

Figure 1
Figure 1
Metabolic pathway showing the O-demethylation and N-demethylation of hydrocodone to hydromorphone and norhydrocodone, respectively. The structure of codeine is also depicted
Figure 2
Figure 2
A) Eadie-Hofstee plot of hydromorphone formation in livers fromCYP2D6 EM (▪) and PM (▴) (V/[S] is multiplied by a factor of 50 to allow it to fit on the same graph). B) Michaelis-Menten plot of (V vs[S] mm) hydromorphone formation in livers fromCYP2D6 EM and PM. C) Eadie-Hofstee plot of norhydrocodone formation in livers fromCYP2D6 EM. D) Michaelis-Menten kinetic profile of norhydrocodone formation in a liver from aCYP2D6 EM. HLS# 21 was the liver from theCYP2D6 EM. [S] represents the hydrocodone concentration. Error bars indicate SD of duplicate samples
Figure 3
Figure 3
Percent contribution of the three oxidative metabolic pathways: hydromorphone high (formula image) and low affinity (▪) sites and norhydrocodone (□), in hydrocodone metabolism. Data were obtained from division of the intrinsic clearance of each pathway by the sum of the calculated intrinsic clearances
Figure 4
Figure 4
Inhibition of hydromorphone (A) and norhydrocodone (B) formation by a range of chemical inhibitors in liver microsomes fromCYP2D6 EM subjects. Error bars indicate SD of duplicate samples. *P < 0.05
Figure 5
Figure 5
Inhibition of hydromorphone (▪) and norhydrocodone (□) formation by monoclonal antibodies directed towards human CYPs. Error bars indicate SD of duplicate samples. *P < 0.05
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