The pharmacokinetics of oxycodone after intravenous injection in adults.

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

doi:10.1111/j.1365-2125.1991.tb03942.x

Cited by 108 publications

(45 citation statements)

References 8 publications

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“…Scale-up of our in vitro, microsomal intrinsic clearance values (excluding the data from CYP3A-deficient HLM 146) predicted an in vivo hepatic clearance that was in excellent agreement with the i.v. oxycodone clearance (i.e., within 80 -112% of the reported value of 0.78 l/min) (Poyhia et al, 1991). In the human intestinal microsomes, oxycodone oxidation occurred at a much lower rate than that in the human liver microsomes.…”

Section: Discussionmentioning

confidence: 85%

“…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%

“…Oxycodone is extensively metabolized; only 10% of dose is excreted unchanged in urine (Poyhia et al, 1991;Kirvela et al, 1996). The known metabolic scheme of oxycodone is presented in Fig.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 85%

Section: Lalovic Et Almentioning

confidence: 99%

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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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“…15) In this study, the pharmacokinetic parameters of oxycodone and hydrocotarnine were calculated and determined for the mobilizing factor of drug clearance to design a detailed dosage for each condition. As a result, oxycodone pharmacokinetic parameters were calculated as follows: CLϭ37.9 l/h, V d ϭ226.7 l. Compared with the value reported in other countries (CL; 46.8 l/h, V d ; 2.6 l/kg), 16) CL showed a low value and V d showed a high value. Oxycodone clearance was low in our patients with cancer pain.…”

Section: Discussionmentioning

confidence: 99%

“…17) One of the impediments that reduces oxycodone clearance is aging, which causes a decrease in renal and hepatic functions. Oxycodone clearance may also be considerably altered with changes in liver blood flow because of the high clearance of 46.8 l/h (ϭ780 ml/min), 16) and accordingly it is expected to decrease when hepatic blood flow is impaired. However, taking account of the high bioavailability of 60% 18) and 87%, 19) the oxycodone clearance, a metabolized amount of oxycodone, is overestimated and unlikely to be that large.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Variation in the Clearance of Oxycodone and Hydrocotarnine in Patients with Cancer Pain

Kokubun

Fukawa

Matoba

et al. 2007

Biological & Pharmaceutical Bulletin

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Compound injections of oxycodone and hydrocotarnine are currently used as one of the treatment options for some cases with cancer pain. However, there have been no reports examining the factors that influence oxycodone and hydrocotarnine clearance, so detailed examination is necessary. As for hydrocotarnine, there have been no reports examining the pharmacokinetics. Therefore in this study, we determined the pharmacokinetics of oxycodone and hydrocotarnine in patients with cancer pain. The study was conducted on 19 patients, in whom pain control was attempted by using the compound injections of oxycodone and hydrocotarnine. We used HPLCelectrochemical detector (ECD) to determine oxycodone and hydrocotarnine serum concentrations, and used the nonlinear least-squares method (MULTI) for calculation of the pharmacokinetic parameters. Furthermore, we examined the factors that influence the clearance of oxycodone and hydrocotarnine by multiple regression analysis (step wise method). The pharmacokinetic parameters were as follows: Oxycodone; V d ‫5.501؎7.622؍‬ l (mean؎S.D.), CL‫1.52؎9.73؍‬ l/h, t 1/2 ‫9.1؎1.4؍‬ h. Hydrocotarnine; V d ‫2.732؎8.672؍‬ l, CL‫3.46؎1.59؍‬ l/h, t 1/2 ‫7.0؎0.2؍‬ h. The clearance of oxycodone represented by a regression formula was significantly correlated to the age, the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance of hydrocotarnine represented by a regression formula was significantly correlated to the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance also indicated that oxycodone concentration in the blood was likely to be higher in patients having these factors. Oxycodone/hydrocotarnine compound injections should be used with caution and dose reduction may be necessary in such populations.

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Oxycodone

Sands

2013

Handbook of Metabolic Pathways of Xenobiotics

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The pharmacokinetics of oxycodone after intravenous injection in adults.

Cited by 108 publications

References 8 publications

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

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

Pharmacokinetics and Variation in the Clearance of Oxycodone and Hydrocotarnine in Patients with Cancer Pain

Oxycodone

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