Abstract:
Fentanyl (FT) is a synthetic μ-opioid receptor agonist, widely used for surgical analgesia and sedation. FT undergoes rapid and extensive hepatic biotransformation to metabolites that result from hydrolysis, N-delalkylation and hydroxylation reactions. The major metabolite is norfentanyl (NFT) formed from N-delakylation. CYP3A4 is responsible for the oxidative dealkylation of FT in the human liver suggesting that FT may be subject to drug interactions in vivo as numerous other therapeutic agents including nifedipine, lidocaine and paracetamol are metabolized by the same enzyme. The toxicity of FT may be in part due to CYP3A4*1B and CYP3A5*3 variant alleles, resulting into variation in FT metabolism. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that FT and all its metabolites have large LUMO-HOMO energy differences so that they would be kinetically inert. However, the molecular surfaces of FT, PAL and NFT are found to abound in electron-deficient regions so that they may be subject to nucleophilic attack by glutathione and nucleobases in DNA resulting into glutathione depletion and DNA damage, respectively. The kinetic inertness of the molecules means that the rates of such adverse reactions would be low unless the reactions are speeded up enzymatically.
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