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. 2019 Jan;12(1):39-46.
doi: 10.1111/cts.12598. Epub 2018 Nov 26.

Effects of Common CYP1A2 Genotypes and Other Key Factors on Intraindividual Variation in the Caffeine Metabolic Ratio: An Exploratory Analysis

Dan-Dan Tian  1 , Senthil Natesan  1 , John R White , Jr  2 , Mary F Paine  1
Affiliations

Effects of Common CYP1A2 Genotypes and Other Key Factors on Intraindividual Variation in the Caffeine Metabolic Ratio: An Exploratory Analysis

Dan-Dan Tian et al. Clin Transl Sci. 2019 Jan.

Abstract

The caffeine metabolic ratio is an established marker for cytochrome P450 (CYP) 1A2 activity. Optimal sample size calculation for clinical pharmacokinetic xenobiotic-caffeine interaction studies requires robust estimates of interindividual and intraindividual variation in this ratio. Compared with interindividual variation, factors contributing to intraindividual variation are less defined. An exploratory analysis involving healthy nonsmoking non-naïve caffeine drinkers (1-3 cups/day; 12 men, 12 women) administered caffeine (160 mg) on five occasions evaluated the effects of CYP1A2 induction status (based on genotype) and other factors on intraindividual variation in CYP1A2 activity. Results were compared with those from previous studies. Regardless of whether a hyperinducer (CYP1A2*1A/*1F or CYP1A2*1F/*1F) or normal metabolizer (CYP1A2*1A/*1A, CYP1A2*1C/*1F, or CYP1A2*1C*1F/*1C*1F), sex, age, oral contraceptive use by women, and smoking status, intraindividual variation was ≤30%. A value of 30% is proposed for optimal design of pharmacokinetic xenobiotic-caffeine interaction studies. Prospective studies are needed for confirmation.

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Figures

Figure 1
Figure 1
Primary metabolic pathways of caffeine.
Figure 2
Figure 2
Box‐and‐whisker plots of C4 h, PX/C4 h, CAF (a) and AUC 0‐8 h, PX/AUC 0‐8 h, CAF (b) ratios for each study arm among men and women. Arm A, hot coffee consumed over 20 minutes; arm B, cold coffee consumed over 2 minutes; arm C, cold coffee consumed over 20 minutes; arm D, energy drink consumed over 2 minutes; and arm E, energy drink consumed over 20 minutes. Lines inside the boxes denote medians, ends of boxes denote 25th and 75th percentiles, whiskers denote 1.5 times the interquartile distance, and circles denote outliers. A sex difference was detected (P < 0.05; Wilcoxon‐Mann‐Whitney U‐test) within each treatment arm when oral contraceptive–using women were included.
Figure 3
Figure 3
Box‐and‐whisker plots of C4 h, PX/C4 h, CAF (a) and AUC 0‐8 h, PX/AUC 0‐8 h, CAF (b) ratios for each study arm among CYP1A2 hyperinducers (Hyper) and normal metabolizers (Normal). Arm A, hot coffee consumed over 20 minutes; arm B, cold coffee consumed over 2 minutes; arm C, cold coffee consumed over 20 minutes; arm D, energy drink consumed over 2 minutes; and arm E, energy drink consumed over 20 minutes. Lines inside the boxes denote medians, ends of boxes denote 25th and 75th percentiles, whiskers denote 1.5 times the interquartile distance, and circles denote outliers. No differences were detected within each treatment arm (P > 0.05; Wilcoxon‐Mann‐Whitney U‐test).
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