title: The pharmacokinetics of ketobemidone are not affected by CYP2D6 or CYP2C19 phenotype.
abstract: The pharmacokinetics of orally administered ketobemidone were investigated in three groups of healthy volunteers with respect to cytochrome P450 (CYP) 2D6 and CYP2C19 phenotypes: extensive metabolisers (EMs) of debrisoquine and mephenytoin (EMdeb/EMmeph), poor metabolisers (PMs) of debrisoquine (PMdeb/EMmeph) and poor metabolisers of mephenytoin (PMmeph/EMdeb). Peak plasma concentration, oral clearance, area under the plasma concentration-time curve, half-life, volume of distribution and mean residence time were not significantly different among the three groups. There was no correlation between oral clearance of ketobemidone and debrisoquine or mephenytoin metabolic ratios. Further, the urinary excretion of ketobemidone and norketobemidone was not affected by the phenotype for either CYP2D6 or CYP2C19. However, a substantial variation in plasma concentration was observed within all three groups. The results indicate that the metabolism of ketobemidone is not dependent on CYP2D6 or CYP2C19. PMs of debrisoquine or mephenytoin, as well as patients who are concomitantly treated with inhibitors of CYP2D6 or CYP2C19, are not expected to be at higher risk of adverse effects. However, due to the interindividual variability in plasma levels of ketobemidone, independent of phenotype, individual dosing based on the clinical response and therapeutic drug monitoring is recommended.
authors.affiliation: Department of Medical Laboratory Sciences and Technology, Huddinge University Hospital, Stockholm, Sweden. ayman.al-shurbaji@pharmlab.hs.sll.se
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Shurbaji
authors.forename: Juliette
authors.initials: J
authors.lastname: Säwe
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008614:Meperidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006899:Mixed Function Oxygenases / Q000502:physiology*; D009061:Mouth Mucosa / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D003577:Cytochrome P-450 Enzyme System; D008614:Meperidine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; C012394:ketobemidone