Dose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans.

Following 49 h of sleep deprivation, 37 healthy males ingested either 2.1, 4.3, or 8.6 mg*kg-1 body weight of caffeine in a randomized double-blind design. Subjects were sleep deprived for additional 12 h and venous blood samples were collected intermittently. Caffeine and primary metabolite concentrations were determined by HPLC. Pharmacokinetics were computed using the Lagran computer program. The ratio of the primary human metabolite, paraxanthine, to caffeine was used to estimate the rate of metabolism. There was a significant (p < 0.05) and disproportional increase in the dose normalized caffeine AUC and a significant decrease in its clearance associated with increasing dose. In addition, the paraxanthine to caffeine ratio significantly decreased with an increase in dose, indicating that the rate of caffeine metabolism decreased. These results demonstrate that under the conditions of severe sleep deprivation caffeine exhibits dose-dependent pharmacokinetics. In addition, these results are consistent with a model of capacity-limited metabolism.

Effects of chronic hypoxia on the pharmacokinetics of caffeine and cardio-green in micro swine.

METHODS: The pharmacokinetics of caffeine and cardio-green (ICG) were examined in four micro swine at sea level (SEA) and following 21 d continuous exposure to 4600 m (ALT) in a hypobaric chamber. Caffeine (84.7 mg) and ICG (10 mg) were administered as separate intravenous boluses and sequential blood samples collected. RESULTS: Caffeine clearance significantly (p < 0.05) increased in ALT (96.8 +/- 20.0 ml.min-1) as compared to SEA (53.6 +/- 24.8 ml.min-1), demonstrating that liver function increased in ALT. There was no significant change in the ratio of primary metabolites to caffeine, suggesting that the increase in clearance was not due to a change in the rate of caffeine metabolism. ICG clearance significantly increased in ALT (179.8 +/- 57.4 ml.min-1) as compared to SEA (84.4 +/- 28.9 ml.min-1) indicating that hepatic blood flow (HBF) increased. CONCLUSION: These results demonstrate that chronic exposure to 4600 m increases the clearance of caffeine and ICG in the micro swine model and suggests that the increase in caffeine clearance is related to HBF.

Effects of altitude (4300 m) on the pharmacokinetics of caffeine and cardio-green in humans.

The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardio-green (ICG) were examined in eight healthy males (23-35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg. kg-1) was administered as an intravenous bolus and caffeine (4 mg. kg-1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in a caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g.l-1.min-1), and increased clearance (117 vs 86 ml.min-1.70 kg-1). In ALT the area under the curve the ICG significantly decreased (85 vs 207 mg.l-1.min-1) and the volume of distribution and clearance increased (5.2 vs 2.4 l and 532 vs 234 ml.min-1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.