The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects.

Pöyhiä, Reino; Seppαlä, Timo; Olkkola, Klaus T.; Kalso, Eija

doi:10.1111/j.1365-2125.1992.tb04090.x

Cited by 252 publications

(113 citation statements)

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“…However, a rapid fall of plasma oxycodone concentrations to below the detection limit might have resulted in underestimation of tl,2,z. Compared with values of clearance in adults, those of children were almost 50% higher [5][6][7] and values of Vss were 18% lower.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative children [see comments]

Olkkola

Hamunen

Seppαlä

et al. 1994

Brit J Clinical Pharma

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Section: Discussionmentioning

confidence: 99%

“…Its use in children is also increasing, although its analgesic efficacy has not been studied in paediatric patients. The pharmacokinetics of oxycodone have been reported only in adults [5][6][7]. We have studied the pharmnacokinetics and ventilatory effects of oxycodone given intravenously to children after ophthalmic surgery.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative children [see comments]

Olkkola

Hamunen

Seppαlä

et al. 1994

Brit J Clinical Pharma

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“…Very low (Ͻ2 ng/ml) circulating concentrations of oxymorphone have been observed following a single oral dose of oxycodone; the AUC ratios oxymorphone to parent drug were Ͻ0.01. On the other hand, plasma noroxycodone concentrations were reported to be significantly higher and comparable with the parent drug; noroxycodone to parent AUC ratios were slightly above unity (Poyhia et al, 1991(Poyhia et al, , 1992Kaiko et al, 1996;Heiskanen et al, 1998). A low presence of circulating oxymorphone could either be explained by its limited formation or efficient clearance (i.e., 3-O-glucuronidation).…”

Section: Lalovic Et Almentioning

confidence: 99%

Quantitative Contribution of Cyp2d6 and Cyp3a to Oxycodone Metabolism in Human Liver and Intestinal Microsomes

Lalovic¹,

Phillips²,

Risler³

et al. 2004

Drug Metab Dispos

234

215

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Oxycodone undergoes N-demethylation to noroxycodone and Odemethylation to oxymorphone. The cytochrome P450 (P450) isoforms capable of mediating the oxidation of oxycodone to oxymorphone and noroxycodone were identified using a panel of recombinant human P450s. CYP3A4 and CYP3A5 displayed the highest activity for oxycodone N-demethylation; intrinsic clearance for CYP3A5 was slightly higher than that for CYP3A4. CYP2D6 had the highest activity for O-demethylation. Multienzyme, Michaelis-Menten kinetics were observed for both oxidative reactions in microsomes prepared from five human livers. Inhibition with ketoconazole showed that CYP3A is the high affinity enzyme for oxycodone N-demethylation; ketoconazole inhibited >90% of noroxycodone formation at low substrate concentrations. CYP3A-mediated noroxycodone formation exhibited a mean K m of 600 ؎ 119 M and a V max that ranged from 716 to 14523 pmol/mg/min. Contribution from the low affinity enzyme(s) did not exceed 8% of total intrinsic clearance for N-demethylation. Quinidine inhibition showed that CYP2D6 is the high affinity enzyme for O-demethylation with a mean K m of 130 ؎ 33 M and a V max that ranged from 89 to 356 pmol/mg/min. Activity of the low affinity enzyme(s) accounted for 10 to 26% of total intrinsic clearance for O-demethylation. On average, the total intrinsic clearance for noroxycodone formation was 8 times greater than that for oxymorphone formation across the five liver microsomal preparations (10.5 l/min/mg versus 1.5 l/min/mg). Experiments with human intestinal mucosal microsomes indicated lower N-demethylation activity (20-50%) compared with liver microsomes and negligible O-demethylation activity, which predict a minimal contribution of intestinal mucosa in the first-pass oxidative metabolism of oxycodone.

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“…Oxycodone, for instance, is structurally similar (see Fig. 1) to codeine and undergoes similar metabolism (Weinstein and Gaylord, 1979;Ishida et al, 1982;Poyhia et al, 1992); thus, it was hypothesized that it too would require O-demethylation at the 3-position to produce analgesia. Studies in humans, however, suggest that oxycodone, and not its O-demethylated derivative, is responsible for analgesia (Kaiko et al, 1996).…”

mentioning

confidence: 99%

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

Thompson¹,

Wojno²,

Greiner³

et al. 2003

J Pharmacol Exp Ther

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Phenotypic differences in analgesic sensitivity to codeine (3-methoxymorphine) results from polymorphisms in cytochrome P450 -2D6, which catalyzes O-demethylation of codeine to morphine. However, O-demethylation reportedly is not required for analgesic activity of the 7,8-saturated codeine congeners dihydrocodeine, hydrocodone, and oxycodone. This study determined the potency and efficacy of these compounds and their demethylated derivatives to stimulate -and ␦-opioid receptor-mediated G-protein activation using agonist-stimulated guanosine 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding. Results showed that 7,8-saturated codeine congeners were more efficacious than codeine in activating -receptors, but only dihydrocodeine was more efficacious at ␦-receptors. Hydrocodone and oxycodone were ϳ10-fold more potent than codeine and dihydrocodeine at either receptor. Morphine-like compounds with a 3-hydroxy group were ϳ30-to 100-fold more potent than their 3-methoxy analogs at the -receptor, and these compounds generally exhibited greater efficacy (e.g., morphine produced 2-fold greater maximal stimulation than codeine). Removal of the N-methyl group did not affect efficacy or potency of codeine congeners to activate -receptors, whereas this modification generally increased efficacy but decreased potency of morphine congeners. At the ␦ receptor, morphine congeners showed greater potency and structuredependent differences in efficacy compared with codeine congeners, whereas removal of the N-methyl group had effects similar to those observed at the -receptor. These results demonstrate that 7,8-saturated codeine congeners are more efficacious than codeine, which may explain their lack of requirement for 3-O-demethylation in vivo. Nonetheless, because all 7,8-saturated codeine congeners were significantly less potent than their morphine derivatives, further research is needed to understand the relationship between metabolism and in vivo activity of these compounds.The opioid analgesic, codeine (3-methoxymorphine), undergoes several metabolic routes including N-and O-demethylation, as well as glucuronidation (Dayer et al., 1988;Mikus et al., 1991;Caraco et al., 1996;Yu et al., 2002). It is well established that codeine must be O-demethylated to morphine to produce analgesia in both humans (Chen et al., 1991) and rats (Mikus et al., 1991;Cleary et al., 1994). In humans, cytochrome P450 -2D6 (CYP-2D6) catalyzes this reaction, and individuals with dysfunctional allelic variants of this gene are phenotypically described as poor metabolizers (PMs) and are less sensitive to codeine. Individuals expressing multiple copies of active CYP-2D6 are extensive metabolizers (EMs) and are more sensitive to codeine. EMs can exhibit the PM phenotype, however, when codeine is coadministered along with a CYP-2D6 inhibitor such as quinidine. The requirement for O-demethylation is not surprising given that the reported K i values for binding to -opioid receptors is 200 times higher for codeine than for morphine (Chen et al., 1991...

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The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects.

Abstract: 1 The pharmacokinetics and metabolism of oxycodone were studied in nine healthy young volunteers in a cross-over study. Each subject received oxycodone chloride once intramuscularly (0.14 mg kg-') and twice orally (0.

Cited by 252 publications

References 20 publications

Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative children [see comments]

Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative children [see comments]

Quantitative Contribution of Cyp2d6 and Cyp3a to Oxycodone Metabolism in Human Liver and Intestinal Microsomes

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

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