PT  - JOURNAL ARTICLE
AU  - Vidya Perera
AU  - Annette S. Gross
AU  - Alan Forrest
AU  - Cornelia B. Landersdorfer
AU  - Hongmei Xu
AU  - Sihem Ait-Oudhia
AU  - Andrew J. McLachlan
TI  - A Pharmacometric Approach to Investigate the Impact of Methylxanthine Abstinence and Caffeine Consumption on CYP1A2 Activity
AID  - 10.1124/dmd.113.053074
DP  - 2013 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1957--1966
VI  - 41
IP  - 11
4099  - http://dmd.aspetjournals.org/content/41/11/1957.short
4100  - http://dmd.aspetjournals.org/content/41/11/1957.full
SO  - Drug Metab Dispos2013 Nov 01; 41
AB  - 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.