title: Delta9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC plasma pharmacokinetics during and after continuous high-dose oral THC.
abstract: BACKGROUND
  Delta(9)-tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis and an active cannabinoid pharmacotherapy component. No plasma pharmacokinetic data after repeated oral THC administration are available.
  
  
  METHODS
  Six adult male daily cannabis smokers resided on a closed clinical research unit. Oral THC capsules (20 mg) were administered every 4-8 h in escalating total daily doses (40-120 mg) for 7 days. Free and glucuronidated plasma THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) were quantified by 2-dimensional GC-MS during and after dosing.
  
  
  RESULTS
  Free plasma THC, 11-OH-THC, and THCCOOH concentrations 19.5 h after admission (before controlled oral THC dosing) were mean 4.3 (SE 1.1), 1.3 (0.5), and 34.0 (8.4) microg/L, respectively. During oral dosing, free 11-OH-THC and THCCOOH increased steadily, whereas THC did not. Mean peak plasma free THC, 11-OH-THC, and THCCOOH concentrations were 3.8 (0.5), 3.0 (0.7), and 196.9 (39.9) mug/L, respectively, 22.5 h after the last dose. Escherichia coli beta-glucuronidase hydrolysis of 264 cannabinoid specimens yielded statistically significant increases in THC, 11-OH-THC, and THCCOOH concentrations (P < 0.001), but conjugated concentrations were underestimated owing to incomplete enzymatic hydrolysis.
  
  
  CONCLUSIONS
  Plasma THC concentrations remained >1 mug/L for at least 1 day after daily cannabis smoking and also after cessation of multiple oral THC doses. We report for the first time free plasma THC concentrations after multiple high-dose oral THC throughout the day and night, and after Escherichia coli beta-glucuronidase hydrolysis. These data will aid in the interpretation of plasma THC concentrations after multiple oral doses.
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, NIH, Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Schwilke
authors.forename: David M
authors.initials: DM
authors.lastname: Schwope
authors.forename: Erin L
authors.initials: EL
authors.lastname: Karschner
authors.forename: Ross H
authors.initials: RH
authors.lastname: Lowe
authors.forename: William D
authors.initials: WD
authors.lastname: Darwin
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kelly
authors.forename: Robert S
authors.initials: RS
authors.lastname: Goodwin
authors.forename: David A
authors.initials: DA
authors.lastname: Gorelick
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D013759:Dronabinol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D004926:Escherichia coli / Q000201:enzymology; D008401:Gas Chromatography-Mass Spectrometry; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: C001427:11-hydroxy-delta(9)-tetrahydrocannabinol; C016780:11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid; D013759:Dronabinol; D005966:Glucuronidase