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

Abstract

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.

Acute hypoxia and cytochrome P450–mediated hepatic drug metabolism in humans

“…This study only tested the effect of hypoxia on the pharmacokinetics of caffeine after long-term (16 weeks) exposure to high altitude (4300 m). 13 In this study hypoxia caused an increase in caffeine clearance (117 versus 86 ml/min per kilogram) and a decrease in caffeine halflife (t 1/2 ) (4.7 versus 6.7 hours) in 8 healthy male subjects, implying an induction of CYP1A2.…”

“…11,12 In contrast, caffeine clearance (also mainly CYP1A2 mediated) increased in healthy subjects after long-term exposure to altitude-induced hypoxemia. 13 Exposure to high altitude has for many years been used as an experimental model of adaptation to hypoxia. After such exposure, arterial PO 2 decreases significantly and several other biologic parameters conform to the general pattern of physiologic adaptation to hypoxia.…”

Caffeine at High Altitude: Java at Base Camp

“…They concluded that the increase in caffeine clearance was owing to increased hepatic blood flow. These same investigators (Kamimori et al, 1995b) then studied the issue in eight males after 16 days at 4300 m. Compared to sea level, the half-life of caffeine decreased from 6.7 to 4.7 h, the area under the curve (AUC) decreased by 32%, and clearance increased 36%. They also reported an increase in the AUC ratio of metabolites to caffeine, suggesting that either metabolite formation or elimination was increased at high altitude.…”

Editorial Comment on: Effect of Altitude on Veteran Suicide Rates by Sabic et al. (From: Sabic H, Kious B, Boxer D, Fitzgerald C, Riley C, Scholl L, McGlade E, Yurgelun-Todd D, Renshaw PF, Kondo DG. High Alt Med Biol 2019;20:171–177; DOI: 10.1089/ham.2018.0130)

“…A number of mechanisms could explain the relationship between suicide or depression and living at altitude (Haws et al, 2009), including the lower blood oxygen saturations that occur at higher altitudes (Katz, 1982;Hackett and Roach, 2012). Indeed, barometric pressure, drug pharmacokinetics, and metabolism-all of which change with altitude-may also affect human behavior, mental health, and suicide risk (Kamimori et al, 1995;Ritschel et al, 1996;Jurgens et al, 2002;Arancibia et al, 2003;Schory et al, 2003;Maldonado et al, 2009).…”