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Research ArticleArticle

A Pharmacometric Approach to Investigate the Impact of Methylxanthine Abstinence and Caffeine Consumption on CYP1A2 Activity

Vidya Perera, Annette S. Gross, Alan Forrest, Cornelia B. Landersdorfer, Hongmei Xu, Sihem Ait-Oudhia and Andrew J. McLachlan
Drug Metabolism and Disposition November 2013, 41 (11) 1957-1966; DOI: https://doi.org/10.1124/dmd.113.053074
Vidya Perera
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.)
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Annette S. Gross
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.)
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Alan Forrest
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.)
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Cornelia B. Landersdorfer
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.)
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Hongmei Xu
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.)
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Sihem Ait-Oudhia
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.)
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Andrew J. McLachlan
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.)
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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.

Footnotes

    • Received June 3, 2013.
    • Accepted August 30, 2013.
  • V.P. is supported by a University at Buffalo/Novartis Postdoctoral Research Fellowship Drug Metabolism and Pharmacokinetics. The original data used in the analysis was funded by the Dr. Peter Coates PhD Scholarship in Clinical Pharmacy and Drug Development supported by GlaxoSmithKline.

  • dx.doi.org/10.1124/dmd.113.053074.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (11)
Drug Metabolism and Disposition
Vol. 41, Issue 11
1 Nov 2013
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Research ArticleArticle

Pharmacometrics of Caffeine and Paraxanthine

Vidya Perera, Annette S. Gross, Alan Forrest, Cornelia B. Landersdorfer, Hongmei Xu, Sihem Ait-Oudhia and Andrew J. McLachlan
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1957-1966; DOI: https://doi.org/10.1124/dmd.113.053074

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Research ArticleArticle

Pharmacometrics of Caffeine and Paraxanthine

Vidya Perera, Annette S. Gross, Alan Forrest, Cornelia B. Landersdorfer, Hongmei Xu, Sihem Ait-Oudhia and Andrew J. McLachlan
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1957-1966; DOI: https://doi.org/10.1124/dmd.113.053074
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