D E Feierman1. 1. Department of Anesthesiology, The Mount Sinai Medical Center, New York, NY 10029-6574, USA. dfeierman@earthlink.net
Abstract
BACKGROUND: Fentanyl is a synthetic opioid widely used in anesthesia and analgesia. In experimental animals and in humans it has been shown that most fentanyl biotransformation occurs in the liver, where this opioid is converted primarily to its N-dealkylated derivative, norfentanyl. Recent studies have shown that fentanyl is metabolized to norfentanyl via cytochrome P-450 3A4 (CYP3A4). CYP3A4 is responsible for the metabolism of numerous other therapeutic agents, including those administered concurrently with fentanyl (e.g., nifedipine, lidocaine, erythromycin and cyclosporine). Paracetamol is also metabolized by the CYP3A family, with a Km that is nearly equal to therapeutic blood concentrations. Since paracetamol is widely used, its potential interaction with fentanyl metabolism would be of great interest. METHODS: In the present study, rat and human liver microsomes were used to assess the ability of paracetamol to inhibit fentanyl metabolism. RESULTS: In both sets of microsomes, paracetamol produced a concentration-dependent inhibition of fentanyl oxidation to norfentanyl. Kinetic analysis of the data showed that 0.5-5 mM paracetamol inhibited fentanyl metabolism in a noncompetitive fashion. A Dixon plot revealed that the Ki for paracetamol inhibition of fentanyl metabolism is approximately 3.2 mM and 2.8 mM for human and rat liver microsomes, respectively. CONCLUSIONS: Since these concentrations of paracetamol are approximately one order of magnitude greater than therapeutic concentrations, it would appear that potentially important and possibly harmful fentanyl-paracetamol drug interactions do not occur with therapeutic concentrations of paracetamol.
BACKGROUND:Fentanyl is a synthetic opioid widely used in anesthesia and analgesia. In experimental animals and in humans it has been shown that most fentanyl biotransformation occurs in the liver, where this opioid is converted primarily to its N-dealkylated derivative, norfentanyl. Recent studies have shown that fentanyl is metabolized to norfentanyl via cytochrome P-450 3A4 (CYP3A4). CYP3A4 is responsible for the metabolism of numerous other therapeutic agents, including those administered concurrently with fentanyl (e.g., nifedipine, lidocaine, erythromycin and cyclosporine). Paracetamol is also metabolized by the CYP3A family, with a Km that is nearly equal to therapeutic blood concentrations. Since paracetamol is widely used, its potential interaction with fentanyl metabolism would be of great interest. METHODS: In the present study, rat and human liver microsomes were used to assess the ability of paracetamol to inhibit fentanyl metabolism. RESULTS: In both sets of microsomes, paracetamol produced a concentration-dependent inhibition of fentanyl oxidation to norfentanyl. Kinetic analysis of the data showed that 0.5-5 mM paracetamol inhibited fentanyl metabolism in a noncompetitive fashion. A Dixon plot revealed that the Ki for paracetamol inhibition of fentanyl metabolism is approximately 3.2 mM and 2.8 mM for human and rat liver microsomes, respectively. CONCLUSIONS: Since these concentrations of paracetamol are approximately one order of magnitude greater than therapeutic concentrations, it would appear that potentially important and possibly harmful fentanyl-paracetamol drug interactions do not occur with therapeutic concentrations of paracetamol.