A.S. Zandvliet(1,2), A.D.R. Huitema(1,2), M.E. de Jonge(1,2), R. den Hoed(3), R.W. Sparidans(3), V.M. Hendriks(4,7), W. van den Brink(5,7), J.M. van Ree(6,7), J.H. Beijnen(1,2,3)
(1)Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands; (2)The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; (3)Department of Biomedical Analysis, Section of Drug Toxicology, Utrecht University, Utrecht, The Netherlands; (4)Parnassia Addiction Research Centre, The Hague, The Netherlands; (5)Amsterdam Institute for Addiction Research, Amsterdam, The Netherlands; (6)Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands; (7)Central Committee on the Treatment of Heroin Addicts (CCBH), Utrecht, The Netherlands
Objectives: The stimulant effect of caffeine, as an additive in legal diacetylmorphine (heroin) preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. From this perspective it is important to obtain insight into the pharmacology of caffeine as an additive to diacetylmorphine after inhalation. The current study focused on the pharmacokinetics of caffeine and its dimethylxanthine metabolites (theobromine, paraxanthine and theophylline) after caffeine inhalation in heroin users.
Methods: Diacetylmorphine preparations (25-100 mg base) containing a 100mg dose of caffeine were used by inhalation in this trial by 10 subjects on 5 consecutive days. For inhalation, either the method of “chasing the dragon” or a laboratory heating plate was used. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography (HPLC). The non-linear mixed effects modelling (NONMEM) program was used to estimate population pharmacokinetic parameters of caffeine and three metabolites simultaneously and their interindividual, interoccasion and intraindividual variabilities. The model was evaluated by the jack-knife procedure.
Results: Caffeine was rapidly and effectively absorbed after inhalation. The process of inhalation could be described as a bolus administration into the central compartment. Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation of the caffeine sublimate could adequately and simultaneously be described by a linear multi-compartment model. Caffeine plasma concentrations were best described by a two compartmental model, its metabolites by single compartment models. The smoking method and the amount of diacetylmorphine that was co-administered with the caffeine did not significantly influence caffeine pharmacokinetics. The extent to which the individual dimethylxanthines were formed was correlated within individuals and subject to high interindividual variability.
Conclusion: The presented model adequately describes the population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation of the caffeine sublimate of a 100mg tablet. Validation by the jack-knife procedure proved the stability of the model.
Reference: PAGE 13 () Abstr 463 [www.page-meeting.org/?abstract=463]
Poster: poster