Pharmacokinetics of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude.

Exposure to high altitude results in significant physiologic changes and may precipitate mountain sickness, ranging from mild symptoms above 2,500 m to severe symptoms above 4,000 m. In a previous study, changes in the pharmacokinetics of meperidine were observed after exposure to high altitude. This study was conducted to investigate whether similar changes occur for acetazolamide, which is prescribed for prophylaxis of acute mountain sickness. Acetazolamide 250 mg was administered orally to young, healthy male volunteers in groups of 12 each: those residing at sea level (group L), these same volunteers on the day after arrival at high altitude (4,360 m, group HA), and volunteers living at high altitude for 10 months or longer (group HC). Serial blood samples were collected for 24 hours and acetazolamide concentrations were measured in whole blood, plasma, and plasma water. The elimination rate constant (lambda z) was significantly increased in group HA compared with group L. Clearance uncorrected for bioavailability (Cl/F) increased significantly in group HA compared with group L, and further increased in group HC. Apparent volume of distribution (Vz/F) was decreased by 17% in group HA compared with group L, and increased by 37% in group HC compared with group HA. Mean residence time (MRT) was significantly decreased in group HA compared with groups L and HC. Erythrocyte (RBC) uptake increased significantly after a significant increase in RBC count in group HC compared with group L. The extent of protein binding (EPB), however, was significantly decreased in group HA compared with groups L and HC. Free acetazolamide concentrations were significantly lower in group HC than in group L 12 hours after administration. Based on these observations, it is suggested that patients travelling to high altitude, especially altitudes above 4,000 m, should be closely monitored and acetazolamide dosage adjusted as necessary.