BACKGROUND Sulfamethoxazole is an antibacterial sulfonamide used primarily for the treatment of a wide variety of bacterial infections in combination with trimethoprim. Despite being used as prophylactic treatment for respiratory infections associated with high altitude, little information is available on the pharmacokinetic properties of sulfamethoxazole in subjects living at high altitude, especially in a Chinese population. OBJECTIVE This study was conducted to investigate the pharmacokinetics of sulfamethoxazole in healthy Chinese subjects after acute and chronic exposure to high altitude. METHODS An open-label, controlled, prospective study was conducted in healthy Chinese male volunteers. Sulfamethoxazole 1200 mg was administered orally to volunteers in 3 groups: those residing at low altitude (approximately 400 m [approximately 1300 ft]); these same volunteers after 16 hours (acute) of exposure to high altitude (approximately 3780 m [approximately 12,400 ft]); and a separate group of volunteers who had been living at high altitude (approximately 3780 m) for >or=1 year (chronic). The phases of the low-altitude and acute-exposure groups were separated by a 1-week washout period. Blood samples were collected from an indwelling venous catheter into heparinized tubes before (baseline) study drug administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours after study drug administration. Sulfamethoxazole in whole blood, plasma, and plasma water, and its metabolite, N(4)-acetyl-sulfamethoxazole, in plasma were determined by HPLC. Tolerability was determined using blood chemistry testing, continuous 12-lead ECG, and blood pressure monitoring. RESULTS A total of 23 healthy Chinese male volunteers living at low altitude (race, all Han Chinese; mean [SD] age, 20.4 [1.1] years [range, 19-24 years]; weight, 64.2 [5.9] kg [range, 56.0-75.0 kg]; and height, 172.1 [4.9] cm [range, 163.0-180.0 cm]) and 21 healthy Chinese male volunteers living at high altitude (race, all Han Chinese; mean [SD] age, 21.2 [1.3] years [range, 19-24 years]; weight, 62.4 [8.2] kg [range, 50.0-75.0 kg]; and height, 171.4 [5.8] cm [range, 162.0-182.0 cm]) were enrolled in the study; 20 from each group completed the study. Concentration of sulfamethoxazole in plasma water decreased significantly after exposure to high altitude; therefore, the protein binding was significantly higher in the acute- (80.4%) and chronic-exposure (72.5%) groups compared with the low-altitude group (65.7%; both, P < 0.001). The binding of sulfamethoxazole to red blood cells was 6.0%, 6.9%, and 9.3% in the low-altitude, acute-, and chronic-exposure groups, respectively. The chronic-exposure group was 55% higher than the low-altitude group (P < 0.001). The following values were recorded in the low-altitude, acute-, and chronic-exposure groups after administration of sulfamethoxazole, respectively: mean (SD) t((1/2)), 9.30 (1.11), 10.37 (0.88), and 11.15 (1.53) hours; mean residence time (MRT(0-48)), 12.06 (0.94), 13.15 (0.67), and 13.00 (1.01) hours; elimination rate constant (k(e)), 0.076 (0.010), 0.067 (0.006), and 0.063 (0.009) hours(-1); AUC(0-48), 1202.5 (238.3), 1416.3 (202.6), and 1298.5 (256.0) micro/mL/h; and clearance (CL), 1.01 (0.22), 0.83 (0.13), and 0.92 (0.22) L/kg/h. The t((1/2)) was 11.5% and 19.9% higher in the acute- and chronic-exposure groups, respectively, compared with the low-altitude group, and 7.5% higher in the chronic-exposure group than in the acute-exposure group. MRT was 9.0% and 7.8% higher in the acute- (P < 0.05) and chronic-exposure (P < 0.001) groups, respectively, than in the low-altitude group. AUC(0-48) was 17.8% higher and CL was 17.8% lower in the acute-exposure group compared with the low-altitude group (both, P < 0.05). CONCLUSIONS This study found significant changes in the disposition of sulfamethoxazole in these healthy male Chinese subjects after either acute or chronic exposure to an altitude of approximately 3780 m in comparison to those residing at an altitude of approximately 400 m.