title: A pharmacometric approach to investigate the impact of methylxanthine abstinence and caffeine consumption on CYP1A2 activity.
abstract: This study aimed to investigate the impact of methylxanthine abstinence (MA) periods on CYP1A2 activity in individuals with varying levels of caffeine consumption through development of a population pharmacokinetic model of caffeine and its major metabolite paraxanthine. This study developed and evaluated a mixed-effects pharmacokinetic model for caffeine and paraxanthine concentration-time data derived from a sequential single-dose cross-over study in healthy male volunteers (n = 30) who received oral 100 mg caffeine doses. Participants received caffeine with and without a MA period. Participants were classified as low (0-100 mg/d), medium (100-200 mg/d), or high (>200 mg/d) caffeine consumers (LCCs, MCCs, or HCCs, respectively). All caffeine and paraxanthine concentration-time data were simultaneously modeled. Caffeine pharmacokinetics was described by a two-compartment model with first-order absorption and two first-order elimination pathways. Paraxanthine was described by a one-compartment model with first-order absorption and elimination. Among LCCs (n = 16) and MCCs (n = 9), there was no difference in the mean (95% confidence interval) total apparent caffeine clearance (CL) between the MA period [LCCs: 6.88 (5.61-8.16 l/h); MCCs: 10.09 (7.57-12.60 l/h)] versus the no MA period [LCCs: 6.22 (4.97-7.46 l/h); MCCs: 9.68 (7.12-12.24 l/h)]. The mean CL among HCCs (n = 5) was considerably higher in the MA period [10.48 (5.62-15.33 l/h)] compared with the no MA period [6.30 (3.40-9.20 l/h)] (P < 0.05). The decrease in CL in the no MA period among HCC appears to be due to alternative caffeine elimination pathways, rather than CYP1A2.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York (V.P., A.F., S.A.-O.); Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia (V.P., A.S.G., A.J.M.); Centre for Research and Education on Ageing, Concord Hospital, Concord, New South Wales, Australia (V.P., A.J.M.); Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline R&D, Sydney, New South Wales, Australia (A.S.G.); School of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia (C.B.L.); and Clinical Pharmacology and Pharmacometrics, AstraZeneca Pharmaceuticals, Wilmington, Delaware (H.X.).
authors.forename: Vidya
authors.initials: V
authors.lastname: Perera
authors.forename: Annette S
authors.initials: AS
authors.lastname: Gross
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
authors.forename: Hongmei
authors.initials: H
authors.lastname: Xu
authors.forename: Sihem
authors.initials: S
authors.lastname: Ait-Oudhia
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
mesh_terms: D000328:Adult; D002110:Caffeine / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D013806:Theophylline / Q000493:pharmacokinetics; D014970:Xanthines / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D014970:Xanthines; C008514:methylxanthine; D002110:Caffeine; D013806:Theophylline; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; C021183:1,7-dimethylxanthine