Hikaru Sato1, Takafumi Naito2, Takuya Ishida1, Junichi Kawakami1. 1. Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan. 2. Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan. naitou@hama-med.ac.jp.
Abstract
PURPOSE: Elevated serum proinflammatory cytokines are associated with the reduction of cytochrome P450 enzyme (CYP) activity. This study aimed to evaluate the oxycodone pharmacokinetics, central symptoms, and serum proinflammatory cytokines based on cachexia stage in cancer patients. METHODS: Forty-seven cancer patients receiving extended-release oxycodone were enrolled. Predose plasma concentrations of oxycodone and its metabolites were normalized with the daily dose and body weight. The central symptoms and serum level of proinflammatory cytokines were investigated at each cachexia stage. RESULTS: The plasma concentrations of oxycodone in patients with cachexia and refractory cachexia were significantly higher than that in patients with precachexia. The metabolic ratio to noroxycodone in patients with cachexia was significantly lower than that in patients with precachexia. The patients with a higher cachexia stage had a higher serum level of interleukin-6 (IL-6), but not tumor necrosis factor-α and interleukin-1β. The serum IL-6 level was correlated with the plasma concentration of oxycodone and inversely with the metabolic ratio to noroxycodone. The incidence of somnolence was not associated with the plasma oxycodone concentration. In contrast, the cachexia stage and its associated serum IL-6 level were correlated with the incidence of somnolence. CONCLUSIONS: Cancer cachexia raised the plasma exposure of oxycodone through the reduction of CYP3A metabolic pathway. The reduction of CYP3A in cachectic cancer patients was associated with an elevation of serum IL-6. Although cachectic cancer patients with higher serum IL-6 levels had the symptom of somnolence, the alterations in oxycodone pharmacokinetics were not related to the incidence of symptom.
PURPOSE: Elevated serum proinflammatory cytokines are associated with the reduction of cytochrome P450 enzyme (CYP) activity. This study aimed to evaluate the oxycodone pharmacokinetics, central symptoms, and serum proinflammatory cytokines based on cachexia stage in cancerpatients. METHODS: Forty-seven cancerpatients receiving extended-release oxycodone were enrolled. Predose plasma concentrations of oxycodone and its metabolites were normalized with the daily dose and body weight. The central symptoms and serum level of proinflammatory cytokines were investigated at each cachexia stage. RESULTS: The plasma concentrations of oxycodone in patients with cachexia and refractory cachexia were significantly higher than that in patients with precachexia. The metabolic ratio to noroxycodone in patients with cachexia was significantly lower than that in patients with precachexia. The patients with a higher cachexia stage had a higher serum level of interleukin-6 (IL-6), but not tumor necrosis factor-α and interleukin-1β. The serum IL-6 level was correlated with the plasma concentration of oxycodone and inversely with the metabolic ratio to noroxycodone. The incidence of somnolence was not associated with the plasma oxycodone concentration. In contrast, the cachexia stage and its associated serum IL-6 level were correlated with the incidence of somnolence. CONCLUSIONS:Cancer cachexia raised the plasma exposure of oxycodone through the reduction of CYP3A metabolic pathway. The reduction of CYP3A in cachectic cancerpatients was associated with an elevation of serum IL-6. Although cachectic cancerpatients with higher serum IL-6 levels had the symptom of somnolence, the alterations in oxycodone pharmacokinetics were not related to the incidence of symptom.
Entities:
Keywords:
CYP3A4; Cancer cachexia; Central symptom; Interleukin-6; Oxycodone; Pharmacokinetics
Authors: K K Machavaram; L M Almond; A Rostami-Hodjegan; I Gardner; M Jamei; S Tay; S Wong; A Joshi; J R Kenny Journal: Clin Pharmacol Ther Date: 2013-04-10 Impact factor: 6.875
Authors: Edward T Morgan; Kerry B Goralski; Micheline Piquette-Miller; Kenneth W Renton; Graham R Robertson; Madhusudana R Chaluvadi; Kellie A Charles; Stephen J Clarke; Marina Kacevska; Christopher Liddle; Terrilyn A Richardson; Rohini Sharma; Christopher J Sinal Journal: Drug Metab Dispos Date: 2008-02 Impact factor: 3.922