In Vivo Activity of Norhydrocodone: An Active Metabolite of Hydrocodone

Abstract

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.

Quantitative determination of opioids in whole blood using fully automated dried blood spot desorption coupled to on‐line SPE‐LC‐MS/MS

“…Another study reports a maximum peak concentration of 23.6 ± 5.2 ng/mL serum achieved at 1.3 ± 0.3 h (t max ) after a 10 mg oral dose of hydrocodone administered to five adult male subjects. The elimination half‐life (t 1/2 ) for hydrocodone following oral administration in humans is around 4 h for hydrocodone and 8 h for norhydrocodone …”

“…The elimination half-life (t 1/2 ) for hydrocodone following oral administration in humans is around 4 h for hydrocodone and 8 h for norhydrocodone. [38,39,49] We observed a maximum peak concentration in blood of 44.9 ± 1.9 ng/mL hydrocodone and 7.7 ± 0.3 ng/mL norhydrocodone 1 h after intake (Figure 4). These concentrations were reduced by approximately 50% after another 3 h and 8 h for hydrocodone and norhydrocodone respectively (20.5 ± 1.0 ng/mL hydrocodone was measured 4 h after intake and 3.3 ± 0.4 ng/mL norhydrocodone 9 h after intake).…”

Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone

“…Interestingly, our acute ED 50 values for hydrocodone are between values reported by two other studies that used the radiantheat tail-flick assay rather than warm-water tail immersion. Kolesnikov et al (2003) found an ED 50 value of 1.37 mg/kg in Swiss Webster mice bred by a different vendor, whereas Navani and Yoburn (2013) calculated an ED 50 value of 11 mg/kg in CD-1 mice.…”

Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers

“…Plasma was separated by centrifugation at 2°C within one hour of collection, transferred into polypropylene tubes, and stored at −20°C to −80°C until analysis was performed. Concentrations in plasma of HC and its minor, though active O-demethylated metabolite, hydromorphone, 12 , 13 were determined by a validated assay using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) (Bioanalytical Services, Athlone, Republic of Ireland). Following solid-phase extraction of HC, hydromorphone, and internal deuterated standards, samples were reconstituted in trifluoroacetic acid and acetonitrile, and loaded onto a liquid chromatography system equipped with a Sciex mass spectrometer.…”