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Comparison of the Pharmacokinetics of Oxycodone and Noroxycodone in Male Dark Agouti and Sprague–Dawley Rats: Influence of Streptozotocin-Induced Diabetes

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Purpose

The aims of this study are to evaluate whether cytochrome P450 (CYP)2D1/2D2-deficient dark agouti (DA) rats and/or CYP2D1/2D2-replete Sprague–Dawley (SD) rats are suitable preclinical models of the human, with respect to mirroring the very low plasma concentrations of metabolically derived oxymorphone seen in humans following oxycodone administration, and to examine the effects of streptozotocin-induced diabetes on the pharmacokinetics of oxycodone and its metabolites, noroxycodone and oxymorphone, in both rodent strains.

Methods

High-performance liquid chromatography–electrospray ionization–tandem mass spectrometry was used to quantify the serum concentrations of oxycodone, noroxycodone, and oxymorphone following subcutaneous administration of bolus doses of oxycodone (2 mg/kg) to groups of nondiabetic and diabetic rats.

Results

The mean (±SEM) areas under the serum concentration vs. time curves for oxycodone and noroxycodone were significantly higher in DA relative to SD rats (diabetic, p < 0.05; nondiabetic, p < 0.005). Serum concentrations of oxymorphone were very low (<6.9 nM).

Conclusions

Both DA and SD rats are suitable rodent models to study oxycodone’s pharmacology, as their systemic exposure to metabolically derived oxymorphone (potent μ-opioid agonist) is very low, mirroring that seen in humans following oxycodone administration. Systemic exposure to oxycodone and noroxycodone was consistently higher for DA than for SD rats showing that strain differences predominated over diabetes status.

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Abbreviations

AUC:

area under the serum concentration vs. time curve for parent drug or metabolite

AUC0–t:

area under the serum concentration vs. time 0, until the time of the last quantifiable serum drug/metabolite concentration

AUCt–∞:

area in the tail of the serum concentration vs. time curve for parent drug or metabolite; , terminal elimination rate constant

C last :

last quantifiable serum drug/metabolite concentration

C max :

maximum serum drug/metabolite concentration

CNS:

central nervous system

CYP:

cytochrome P450

DA:

dark agouti

HPLC–ESI–MS–MS:

high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry

SD:

Sprague–Dawley

SEM:

standard error of the mean

STZ:

streptozotocin

t 1/2 abs :

absorption half-life

t 1/2 elim :

terminal elimination half-life

T max :

time of maximum serum drug/metabolite concentration

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Acknowledgments

The authors wish to thank Ms. Loan Le and Ms. Margaret Patterson for their excellent technical assistance and Dr. Stephen Duffull for helpful pharmacokinetic advice.

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Authors and Affiliations

  1. School of Pharmacy, University of Queensland, Brisbane, 4072, Queensland, Australia

    Lillian Huang, Stephen R. Edwards & Maree T. Smith

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  1. Lillian Huang
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  2. Stephen R. Edwards
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  3. Maree T. Smith
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Correspondence to Maree T. Smith.

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Huang, L., Edwards, S.R. & Smith, M.T. Comparison of the Pharmacokinetics of Oxycodone and Noroxycodone in Male Dark Agouti and Sprague–Dawley Rats: Influence of Streptozotocin-Induced Diabetes. Pharm Res 22, 1489–1498 (2005). https://doi.org/10.1007/s11095-005-6154-y

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  • DOI: https://doi.org/10.1007/s11095-005-6154-y

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