title: Disposition in humans of racemic picenadol, an opioid analgesic.
abstract: Racemic picenadol is being tested clinically as an analgesic. The (+)-enantiomer of picenadol is an opioid agonist and the (-)-enantiomer is a weak agonist/antagonist. The disposition of racemic [14C] picenadol was studied in healthy men after a single dose was administered im (N = 3) and orally (N = 5). After the dose, virtually none of the radioactivity that appeared in blood was associated with the red cells. In plasma, approximately 4% of the radioactivity was attributable to the parent drug, the remainder being picenadol glucuronide (approximately 35%) and other metabolites. The t1/2 for total radioactivity was 6 hr, that for the unchanged drug was 3.5 hr. Picenadol was present in plasma almost exclusively as the (+)-enantiomer. However, after incubation with glucuronidase and sulfatase, plasma contained 2 to 4 times more (-)- than (+)-picenadol, indicating that more conjugated (-)-picenadol than conjugated (+)-picenadol was in the plasma. After im and oral administration of [14C]picenadol, plasma levels of radioactivity were generally 10 and 70 times higher than those in saliva, respectively. More than 90% of the administered radioactivity was excreted in the urine, mostly as picendol glucuronide, and lesser amounts of picenadol sulfate and N-desmethylpicenadol sulfate. Only about 1% of the administered dose of picenadol appeared unchanged in urine. The disposition of racemic picenadol in humans was stereoselective, the (-)-picenadol apparently being metabolized preferentially over the (+)-enantiomer. This finding was of particular interest in view of the dissimilar pharmacologic activities of the enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Lilly Laboratory for Clinical Research, Eli Lilly and Co., Indianapolis, IN.
authors.forename: P M
authors.initials: PM
authors.lastname: Franz
authors.forename: S L
authors.initials: SL
authors.lastname: Anliker
authors.forename: J T
authors.initials: JT
authors.lastname: Callaghan
authors.forename: K A
authors.initials: KA
authors.lastname: DeSante
authors.forename: P H
authors.initials: PH
authors.lastname: Dhahir
authors.forename: R L
authors.initials: RL
authors.lastname: Nelson
authors.forename: A
authors.initials: A
authors.lastname: Rubin
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000700:Analgesics / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005965:Glucuronates / Q000378:metabolism; D005966:Glucuronidase; D006801:Humans; D006868:Hydrolysis; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes; D010880:Piperidines / Q000493:pharmacokinetics*; D012463:Saliva / Q000378:metabolism; D013237:Stereoisomerism; D013429:Sulfatases; D013431:Sulfates / Q000378:metabolism
chemical_list: D000700:Analgesics; D005965:Glucuronates; D009097:Multienzyme Complexes; D010880:Piperidines; D013431:Sulfates; C023059:glusulase; D013429:Sulfatases; D005966:Glucuronidase; C035115:picenadol