PHARMACOKINETICS OF ACETAZOLAMIDE IN HEALTHY-VOLUNTEERS AFTER SHORT-TERM AND LONG-TERM EXPOSURE TO HIGH-ALTITUDE

Exposure to high altitude results in significant physiologic changes a nd may precipitate mountain sickness, ranging from mild symptoms above 2,500 m to severe symptoms above 4,000 m. In a previous study, change s in the pharmacokinetics of meperidine were observed after exposure t o high altitude. This study was conducted to investigate whether simil ar changes occur for acetazolamide, which is prescribed for prophylaxi s of acute mountain sickness. Acetazolamide 250 mg was administered or ally to young. healthy male volunteers in groups of 12 each: those res iding at sea level (group L), these same volunteers on the day after a rrival 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 mea sured in whole blood, plasma, and plasma water. The elimination rate c onstant (lambda(z)) was significantly increased in group HA compared w ith group L. Clearance uncorrected for bioavailability (Cl/F) increase d significantly in group HA compared with group L, and further increas ed in group HC. Apparent volume of distribution (V-x/F) was decreased by 17% in group HA compared with group L, and increased by 37% in grou p HC compared with group HA. Mean residence time (MRT) was significant ly decreased in group HA compared with groups L and HC. Erythrocyte (R BC) uptake increased significantly after a significant increase in RBC count in group HC compared with group L. The extent of protein bindin g (EPB), however, was significantly decreased in group HA compared wit h groups L and HC. Free acetazolamide concentrations were significantl y lower in group HC than in group L 12 hours after administration. Bas ed on these observations, it is suggested that patients travelling to high altitude, especially altitudes above 4,000 m, should be closely m onitored and ac,acetazolamide dosage adjusted as necessary. Journal of Clinical Pharmacology, 1998;38:533-539 (C) 1998 The American College of Clinical Pharmacology.