Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer

Susce, Margaret T.; Murray-Carmichael, Elaina; Leon, José de

doi:10.1016/j.pnpbp.2006.03.018

Cited by 98 publications

(55 citation statements)

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“…Genetic alterations in CYP2D6 enzyme activity have also been suggested to influence the pharmacokinetic profile [36] and clinical effects [37][38][39] of oxycodone. In the present study, one of the subjects was an ultrarapid metabolizer via CYP2D6.…”

Section: Discussionmentioning

confidence: 99%

Voriconazole drastically increases exposure to oral oxycodone

Hagelberg

Nieminen

Saari

et al. 2008

Eur J Clin Pharmacol

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Section: Discussionmentioning

confidence: 99%

Voriconazole drastically increases exposure to oral oxycodone

Hagelberg

Nieminen

Saari

et al. 2008

Eur J Clin Pharmacol

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“…Hydrocodone and hydromorphoneinduced pharmacological effects have been well studied in humans and rodents (Small et al, 1938;Murray and Hagen, 2005;Peckham and Traynor, 2006;Susce et al, 2006;Kumar et al, 2008;Madia et al, 2009). In addition, some reports suggest that hydromorphone, an active metabolite of hydrocodone, is primarily responsible for hydrocodone-induced in vivo effects (Otton et al, 1993;Lurcott, 1998).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Activity of Norhydrocodone: An Active Metabolite of Hydrocodone

Navani

Yoburn

2013

J Pharmacol Exp Ther

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Hydrocodone is primarily metabolized to hydromorphone and norhydrocodone. Although hydromorphone is a known active metabolite of hydrocodone, the in vivo activity of norhydrocodone is not well documented. In the current study, the pharmacodynamics of norhydrocodone were evaluated and compared with hydrocodone and hydromorphone. Binding studies established that norhydrocodone, similar to hydrocodone and hydromorphone, is a m-selective opioid ligand. In vivo analgesia studies (tail flick) demonstrated that, following subcutaneous, intrathecal, and intracerebroventricular administration, norhydrocodone produced analgesia. Following subcutaneous administration, norhydrocodone was ∼70-fold less potent, and hydromorphone was ∼5.4-fold more potent than hydrocodone in producing analgesia. Following intrathecal administration, norhydrocodone produced a shallow analgesia dose-response curve and maximal effect of 15-45%, whereas hydrocodone and hydromorphone produced dose-dependent analgesia. Intrathecal hydromorphone was ∼174-fold more potent than intrathecal hydrocodone. Following intracerebroventricular administration, norhydrocodone had similar potency to hydrocodone in producing analgesia, while hydromorphone was ∼96-fold more potent than hydrocodone. Analgesia induced by the three drugs following subcutaneous, intrathecal, and intracerebroventricular administration was antagonized by subcutaneous naltrexone, confirming that it is opioid receptor-mediated. Subcutaneous norhydrocodone-induced analgesia was completely blocked by intracerebroventricular naltrexone, indicating that norhydrocodone-induced analgesia is likely a supraspinal effect. Seizure activity was observed following intrathecal administration of all three drugs. Norhydrocodone and hydromorphone were ∼3.7 to 4.6-fold more potent than hydrocodone in inducing seizure activity. Naltrexone did not antagonize opioid-induced seizure activity, suggesting that seizures were not opioid receptormediated. Taken together, norhydrocodone is an active metabolite of hydrocodone and may contribute to therapeutic and toxic effects following hydrocodone administration.

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“…Two clinical cases have been reported on CYP2D6 PM; these patients achieved analgesia from hydrocodone but not from codeine and oxycodone and that further they tolerated hydrocodone better than codeine, oxycodone, and morphine. 117,118 After administration of hydrocodone, 5% of the dose is recovered in urine as hydromorphone and conjugated hydromorphone and 0.2% as DHM and isodihydromorphine. 114 The major metabolites of hydrocodone excreted into urine are dihydrocodeine and nordihydrocodeine (both conjugated to approximately 65%).…”

Section: Hydrocodonementioning

confidence: 99%