Determination of Oxycodone in Plasma and Identification of a Major Metabolite

Weinstein, Stephen H.; Gaylord, Janet

doi:10.1002/jps.2600680441

Cited by 57 publications

(35 citation statements)

References 4 publications

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“…It has been suggested that some of the analgesic effect of oxycodone might be due to its active metabolites (Kalso et al, 1990). Conjugated oxymorphone and oxycodone, free oxycodone and noroxycodone have been measured in human urine after oral oxycodone (Baselt & Stewart, 1978;Weinstein & Gaylord, 1979). In the present study noroxycodone concentrations were very low.…”

Section: Discussionmentioning

confidence: 42%

“…In the present study noroxycodone concentrations were very low. According to Weinstein & Gaylord (1979), noroxycodone is a considerably weaker analgesic than oxycodone in the dog. Oxymorphone, which is another metabolite of oxycodone (Baselt & Stewart, 1978), is known to be a potent analgesic.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma noroxycodone was measured as a heptafluorobutyric acid anhydride derivative by gas chromatography using a method modified from Weinstein & Gaylord (1979). Toluene was used for extraction and flurazepam served as internal standard.…”

Section: Assays and Pharmacokinetic Analysismentioning

confidence: 99%

“…Noroxycodone (Weinstein & Gaylord, 1979) and oxymorphone (Baselt & Stewart, 1978) are thought to be the main metabolites of oxycodone in man. Although oxycodone has been in clinical use since the 1920s, its pharmacokinetics have not been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

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The pharmacokinetics of oxycodone after intravenous injection in adults.

Pöyhiä

Olkkola

Seppαlä

et al. 1991

Brit J Clinical Pharma

108

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Oxycodone chloride (0.07 mg kg-') was given by intravenous bolus to nine young adult surgical patients on the first postoperative day. Plasma was sampled for up to 12 h. Mean values of tyl/,, CL and Vss were 222 min, 0.78 1 min-1 and 2.60 1 kg-1, respectively. The concentrations of the metabolite noroxycodone was also measured. The mean AUC(0,12) ratio of noroxycodone to oxycodone was 0.33. Oxymorphone was not detected.

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Section: Discussionmentioning

confidence: 42%

Section: Discussionmentioning

confidence: 99%

Section: Assays and Pharmacokinetic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The pharmacokinetics of oxycodone after intravenous injection in adults.

Pöyhiä

Olkkola

Seppαlä

et al. 1991

Brit J Clinical Pharma

108

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“…Oxycodone also undergoes N-demethylation at the 17-position to noroxycodone (Weinstein and Gaylord, 1979;Somogyi, 1999). CYP3A4 is known to catalyze the N-demethylation of codeine (Gorski et al, 1994) and dextromethorphan (Caraco et al, 1996b), but the role of this enzyme in the N-demethylation of oxycodone has not been established.…”

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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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