Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites

Abstract

This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy. A prospective, multicenter PK study was conducted among 59 pregnant women (93.2% white) who were studied once during a trimester. One beverage with 30-95 mg caffeine was consumed, and a blood/urine sample was collected within 1 hour postingestion. Concentrations of caffeine and its primary metabolites were quantified from serum and urine by LC-MS/MS. There was a significant increase in dose-normalized caffeine serum and urine concentrations between the first and third trimesters (P < .05 and P < .01, respectively). Normalized theophylline concentrations also increased significantly in the third trimester in serum (P < .001) and in urine (P < .05). The caffeine urine/serum concentration ratio also increased in the last trimester (P < .05). No significant difference was found in normalized paraxanthine or theobromine concentrations. This study identified decreased caffeine metabolism and an increase in the active metabolite theophylline concentrations during pregnancy, especially in the third trimester, revealing evidence of the large role that pregnancy plays in influencing caffeine metabolism.

Keywords: caffeine; metabolites; pharmacokinetics; pregnancy.

Figure 1

Chemical structure and metabolic pathways of caffeine and its metabolites.^, Parent compound, 1,3,7-trimethylxanthine (137X, caffeine); primary metabolites (pointed to by large arrow) 1,7-dimethylxanthine (17X, paraxanthine), 3,7-dimethylxanthine (37X, theobromine), 1,3-dimethylxanthine (13X, theophylline); secondary metabolites (pointed to by medium arrow) 1-methylxanthine (1X), 3-methylxanthine (3X), 7-methylxanthine (7X), 1,7-dimethyluracil (17U), 1,3-dimethyluracil (13U), 3,7-dimethyluracil (37U), 5-acetylamino-6-formylamino-3-methyluracil (AFMU); tertiary metabolites (pointed to by small arrow) 1-methyluracil (1U), 7-methyluracil (7U), 5-acetylamino-6-amino-3-methyluracil (AAMU); enzymes cytochrome P450 1A2(CYP1A2), cytochrome P450 2E1 (CYP2E1), cytochromeP450 2A6 (CYP2A6), N-acetyltransferase2 (NAT2), xanthine oxidase (XO). Major metabolic pathways of caffeine and its primary metabolites were highlighted by bold arrows.

Figure 2

Concentration-time curves of (A) caffeine, (B) paraxanthine, (C) theobromine, and (D) theophylline in serum per trimester. Concentrations have been normalized to the median dose of 50 mg caffeine. Dots represent a single observation from each patient during a trimester; the line was fitted by a nonlinear second-order polynomial to illustrate the concentration-time trend for each trimester. *P < .05, significant difference in caffeine serum concentrations between first and third trimesters, or significant difference in theophylline serum concentration between second and third trimesters; ***P < .001, significant difference in theophylline serum concentration between first and third trimesters.

Figure 3

Concentration-time curves of (A) caffeine, (B) paraxanthine, (C) theobromine, and (D) theophylline in urine per trimester. Concentrations have been normalized to the median dose of 50 mg caffeine. Dots represent single observations from each patient during a trimester; the line was fitted by a nonlinear second-order polynomial to illustrate the concentration-time trend for each trimester. **P < .01, significant difference in caffeine urine concentrations between first and third trimesters; *P <. 05, significant difference in theophylline urine concentration between first and third trimesters.