CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone

Abstract

The contribution of cytochrome P450 2D6 (CYP2D6) to the formation of hydrocodone's active metabolite, hydromorphone, was examined in vitro and in vivo. Human liver microsomes prepared from an individual homozygous for the D6-B mutation of the CYP2D6 gene catalyzed this reaction at a negligible rate. Urinary metabolic ratios of hydrocodone/hydromorphone were highly correlated with O-demethylation ratios for dextromethorphan, an established marker drug of CYP2D6 activity (rs = 0.85; n = 18). The kinetics of hydrocodone after a single oral dose and its partial metabolic clearance to hydromorphone were investigated in five extensive metabolizers of dextromethorphan, six poor metabolizers, and four extensive metabolizers after pretreatment with quinidine, a selective inhibitor of CYP2D6 activity. The mean values for partial metabolic clearance by O-demethylation in the three groups were 28.1 +/- 10.3, 3.4 +/- 2.4, and 5.0 +/- 3.6 ml/hr/kg, respectively. No statistically significant phenotypic differences in physiologic measures were observed. However, over the first hour after dosing, the extensive metabolizers reported more "good opiate effects" and fewer "bad opiate effects" than poor metabolizers and extensive metabolizers in whom CYP2D6 was inhibited by quinidine. These data establish the importance of CYP2D6 in the formation of hydromorphone from hydrocodone and suggest that the activity of this enzyme may limit the abuse liability of hydrocodone.

Activation of G-Proteins by Morphine and Codeine Congeners: Insights to the Relevance of O- and N-Demethylated Metabolites at μ- and δ-Opioid Receptors

“…A similar conclusion was drawn from studies on psychomotor effects and subject self-reporting of drug experience following oxycodone administration (Heiskanen et al, 1998). Studies examining O-demethylation of hydrocodone to hydromorphone have also shown that the parent compound appears to be responsible for analgesic effects in rats (Tomkins et al, 1997), monkeys (Lelas et al, 1999), and humans (Otton et al, 1993).…”

Transient Low Testosterone Levels After Oral Hydrocodone May Contribute to Misdiagnosis of Hypogonadism

“…The 2 -4 h duration of hydrocodone-induced analgesia [5] and the 3.8 -4.2 h hydrocodone half-life after ingestion of a single 10 mg dose [6,7] are compatible with brief duration of any post-ingestion inhibition of testosterone formation, supporting the possibility that this ingestion shortly before testosterone measurement might jeopardize its value in establishing a diagnosis of hypogonadism.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Other opioids. Production of the active metabolites of hydrocodone (hydromorphone) and oxycodone (oxymorphone) is reduced in CYP2D6 PMs (Otton et al, 1993;Heiskanen et al, 1998). However, there is little evidence of a difference in effect between EMs and PMs in human studies (Otton et al, 1993;Kaplan et al, 1997;Heiskanen et al, 1998) or in animal models (Tomkins et al, 1997;Lelas et al, 1999).…”