Department of Pharmacology, College of Life Science, Shenyang Pharmaceutical University, Shenyang, China.
Clin Ther. 2009 Nov;31(11):2744-54. doi: 10.1016/j.clinthera.2009.11.019.
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.
This study was conducted to investigate the pharmacokinetics of sulfamethoxazole in healthy Chinese subjects after acute and chronic exposure to high altitude.
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.
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).
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.
磺胺甲恶唑是一种用于治疗多种细菌感染的抗菌磺胺类药物，通常与甲氧苄啶联合使用。尽管它被用于预防与高海拔相关的呼吸道感染，但对于居住在高海拔地区的人群，尤其是中国人群，磺胺甲恶唑的药代动力学特性信息很少。
本研究旨在调查健康中国男性志愿者在急性和慢性暴露于高海拔环境后磺胺甲恶唑的药代动力学。
一项开放标签、对照、前瞻性研究在健康的中国男性志愿者中进行。志愿者分为三组，分别接受 1200 mg 磺胺甲恶唑口服给药：一组居住在低海拔（约 400 m[约 1300 英尺]）；同一组志愿者在暴露于高海拔（约 3780 m[约 12400 英尺]）16 小时后；另一组志愿者则在高海拔地区（约 3780 m）居住了> = 1 年（慢性）。低海拔和急性暴露组的阶段之间用 1 周洗脱期隔开。在给予研究药物前（基线）和给予研究药物后 0.25、0.5、0.75、1、1.5、2、3、4、6、8、12、24、36 和 48 小时，从静脉留置导管中采集全血、血浆和血浆水样本，并采用 HPLC 测定磺胺甲恶唑及其代谢物 N（4）-乙酰磺胺甲恶唑在血浆中的浓度。使用血液化学检测、连续 12 导联心电图和血压监测来确定耐受性。
共有 23 名居住在低海拔（种族均为汉族；平均[标准差]年龄 20.4[1.1]岁[范围 19-24 岁]；体重 64.2[5.9]kg[范围 56.0-75.0 kg]；身高 172.1[4.9]cm[范围 163.0-180.0 cm]）和 21 名居住在高海拔（种族均为汉族；平均[标准差]年龄 21.2[1.3]岁[范围 19-24 岁]；体重 62.4[8.2]kg[范围 50.0-75.0 kg]；身高 171.4[5.8]cm[范围 162.0-182.0 cm]）的健康中国男性志愿者被纳入研究；每组各有 20 名志愿者完成了研究。暴露于高海拔后，磺胺甲恶唑在血浆水中的浓度显著下降；因此，急性（80.4%）和慢性（72.5%）暴露组的蛋白结合率明显高于低海拔组（65.7%；均 P < 0.001）。磺胺甲恶唑与红细胞的结合率分别为低海拔组、急性暴露组和慢性暴露组的 6.0%、6.9%和 9.3%。慢性暴露组比低海拔组高 55%（P < 0.001）。磺胺甲恶唑在低海拔、急性和慢性暴露组给药后的 t((1/2))分别为 9.30（1.11）、10.37（0.88）和 11.15（1.53）小时；平均驻留时间（MRT(0-48)）分别为 12.06（0.94）、13.15（0.67）和 13.00（1.01）小时；消除率常数（k(e)）分别为 0.076（0.010）、0.067（0.006）和 0.063（0.009）小时(-1)；AUC(0-48)分别为 1202.5（238.3）、1416.3（202.6）和 1298.5（256.0）μg/mL/h；CL 分别为 1.01（0.22）、0.83（0.13）和 0.92（0.22）L/kg/h。急性暴露组和慢性暴露组的 t((1/2))分别比低海拔组高 11.5%和 19.9%，而慢性暴露组比急性暴露组高 7.5%。MRT 在急性（P < 0.05）和慢性（P < 0.001）暴露组中分别比低海拔组高 9.0%和 7.8%。AUC(0-48)在急性暴露组中比低海拔组高 17.8%，CL 低 17.8%（均 P < 0.05）。
与居住在约 400 m 海拔的人群相比，这些健康的中国男性志愿者在急性或慢性暴露于约 3780 m 海拔后，磺胺甲恶唑的处置发生了显著变化。
