Comparison of the pharmacokinetics of oxycodone and noroxycodone in male dark agouti and Sprague--Dawley rats: influence of streptozotocin-induced diabetes.
OBJECTIVE
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 micro-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.
Huang
Lillian
L
School of Pharmacy, University of Queensland, Brisbane, 4072 Queensland, Australia.
Edwards
Stephen R
SR
Smith
Maree T
MT
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000072467:Cytochrome P450 Family 2; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D008297:Male; D009019:Morphinans / Q000493:pharmacokinetics*; D010098:Oxycodone / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D013311:Streptozocin
D000701:Analgesics, Opioid; D009019:Morphinans; D013311:Streptozocin; C077256:noroxycodone; D010098:Oxycodone; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; C119985:Cyp2d2 protein, rat; D000072467:Cytochrome P450 Family 2