title: Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine.
abstract: The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands. apaza@slz.nl
authors.forename: Anthe S
authors.initials: AS
authors.lastname: Zandvliet
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Milly E
authors.initials: ME
authors.lastname: de Jonge
authors.forename: Rob
authors.initials: R
authors.lastname: den Hoed
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Hendriks
authors.forename: Wim
authors.initials: W
authors.lastname: van den Brink
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Ree
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D001682:Biological Availability; D002110:Caffeine / Q000493:pharmacokinetics*; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D006207:Half-Life; D003932:Heroin / Q000493:pharmacokinetics*; D006556:Heroin Dependence / Q000188:drug therapy; D006801:Humans; D007275:Injections, Intravenous; D008691:Methadone / Q000494:pharmacology; D009294:Narcotics / Q000493:pharmacokinetics*; D011153:Population; D013805:Theobromine / Q000493:pharmacokinetics*; D013806:Theophylline / Q000493:pharmacokinetics*
chemical_list: D000697:Central Nervous System Stimulants; D004338:Drug Combinations; D009294:Narcotics; D002110:Caffeine; D003932:Heroin; D013806:Theophylline; D013805:Theobromine; C021183:1,7-dimethylxanthine; D008691:Methadone