Abstract
Oxycodone is commonly used to treat severe pain in adults and children. It is extensively metabolized in the liver in adults, but the maturation of metabolism is not well understood. Our aim was to study the metabolism of oxycodone in cryopreserved human hepatocytes from different age groups (3 days, 2 and 5 months, 4 years, adult pool) and predict hepatic plasma clearance of oxycodone using these data. Oxycodone (0.1, 1, and 10 μM) was incubated with hepatocytes for 4 h, and 1 μM oxycodone also with CYP3A inhibitor ketoconazole (1 μM). Oxycodone and noroxycodone concentrations were determined at several time points with liquid chromatography–mass spectrometry. In vitro clearance of oxycodone was used to predict hepatic plasma clearance, using the well-stirred model and published physiological parameters. Noroxycodone was the major metabolite in all batches and ketoconazole inhibited the metabolism markedly in most cases. A clear correlation between in vitro oxycodone clearance and CYP3A4 activity was observed. The predicted hepatic plasma clearances were typically much lower than the published median total plasma clearance from pharmacokinetic studies. The data suggests that there are no children-specific metabolites of oxycodone. Moreover, CYP3A activity seems to be the major determinant in metabolic clearance of oxycodone regardless of age group or individual variability in hepatocyte batches.
Highlights
Oxycodone (7,8-dihydro-14-hydroxycodeinone) is a commonly prescribed opioid for severe pain, and during the last years its use has surpassed that of morphine in several countries (International Narcotics Control Board, 2010)
Our aim was to study the metabolism of oxycodone in cryopreserved human hepatocytes from different age groups (3 days, 2 and 5 months, 4 years, adult pool) and predict hepatic plasma clearance of oxycodone using these data
The body surface area (BSA) was calculated from the weight and height using the equation by Haycock et al (1978) when the weight was below 15 kg and the equation from DuBois and DuBois (1916) in other cases
Summary
Oxycodone (7,8-dihydro-14-hydroxycodeinone) is a commonly prescribed opioid for severe pain, and during the last years its use has surpassed that of morphine in several countries (International Narcotics Control Board, 2010). Oxymorphone and noroxymorphone are active metabolites, but they probably do not contribute markedly to the central opioid effects since their plasma concentrations are significantly lower than that of parent compound (Heiskanen et al, 1998; Lalovic et al, 2006; Lemberg et al, 2010). These metabolites are less lipophilic than oxycodone, a characteristic that may limit their uptake into the brain (Lalovic et al, 2006)
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