Comparison of the Pharmacokinetics of Sulfamethoxazole in Male Chinese Volunteers at Low Altitude and Acute Exposure to High Altitude Versus Subjects Living Chronically at High Altitude: An Open-Label, Controlled, Prospective Study
Comparison of the Pharmacokinetics of Sulfamethoxazole in Male Chinese Volunteers at Low Altitude and Acute Exposure to High Altitude Versus Subjects Living Chronically at High Altitude: An Open-Label, Controlled, Prospective Study
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DOI：
10.1016/j.clinthera.2009.11.019
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发表时间：
2009-11-01
影响因子：
3.2
通讯作者：
Ge, Ri-Li
中科院分区：
文献类型：
--
作者：
Li, Xiang-Yang;Gao, Fen;Ge, Ri-Li
背景：磺胺甲恶唑是一种抗菌磺胺类药物，主要用于与甲氧苄啶联合治疗多种细菌感染。尽管磺胺甲恶唑被用作与高海拔有关的呼吸道感染的预防性治疗，但关于磺胺甲恶唑在高海拔地区，特别是在中国人群中的药代动力学特性的信息很少。目的：研究磺胺甲恶唑在中国健康受试者急性和慢性高原暴露后的药代动力学。方法：在中国健康男性志愿者中进行一项开放标签、对照、前瞻性研究。志愿者口服磺胺甲恶唑1200毫克，分为3组：居住在低海拔（约400米[约1300英尺]）；这些志愿者在16小时（急性）暴露于高海拔（约3780米）后；另一组志愿者在高海拔地区（大约3780米）生活了1年（慢性）。低空暴露组和急性暴露组以1周的洗脱期分开。在给药前（基线）和给药后0.25、0.5、0.75、1、1.5、2、3、4、6、8、12、24、36和48小时从留置静脉导管中采集血液。采用高效液相色谱法测定全血、血浆、血浆水中磺胺甲恶唑及其代谢物n -4-乙酰-磺胺甲恶唑的含量。通过血液化学试验、连续12导联心电图和血压监测来确定耐受性。结果：共有23名生活在低海拔地区的健康中国男性志愿者（种族，均为汉族，平均[SD]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]）， 21名生活在高海拔地区的健康中国男性志愿者(种族，均为汉族，平均[SD]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]；身高为171.4 [5.8]cm[范围，162.0-182.0 cm])者纳入研究；每组20人完成研究。高原暴露后血浆水中磺胺甲恶唑浓度显著降低；因此，急性暴露组（80.4%）和慢性暴露组（72.5%）的蛋白结合明显高于低海拔组（65.7%,P < 0.001）。在低海拔、急性和慢性暴露组中，磺胺甲恶唑与红细胞的结合率分别为6.0%、6.9%和9.3%。慢性暴露组比低海拔组高55% （P < 0.001）。低海拔、急性、慢性暴露组给药后的平均（SD） t（1/2）、9.30（1.11）、10.37（0.88）、11.15 (1.53)h；平均停留时间（MRT0-48）、12.06（0.94）、13.15（0.67）、13.00（1.01）小时；消除速率常数（k(e)）、0.076（0.010）、0.067（0.006）、0.063（0.009）小时（-1）；AUC（0-48）、1202.5（238.3）、1416.3（202.6）、1298.5 (256.0)mu g/mL/h；清除率分别为1.01（0.22）、0.83（0.13）、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%，慢性暴露组比急性暴露组高7.5%。急性暴露组和慢性暴露组的MRT分别比低海拔组高9.0% （P < 0.05）和7.8% （P < 0.001）。急性暴露组的AUC（0 ~ 48）比低海拔组高17.8%，CL低17.8%（均P < 0.05）。结论：本研究发现，在急性或慢性暴露于海拔3780 m的健康中国男性受试者中，磺胺甲恶唑的处置与居住在海拔400 m的受试者相比有显著变化。（中国医学杂志，2009;31:2744-2754）
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 (similar to 400 m [similar to 1300 ft]); these same volunteers after 16 hours (acute) of exposure to high altitude (similar to 3780 m [similar to 12,400 ft]); and a separate group of volunteers who had been living at high altitude (similar to 3780 m) for >= l 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 (MRT0-48), 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) mu g/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).Conclusion: 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 similar to 3780 m in comparison to those residing at an altitude of similar to 400 m. (Clin Ther. 2009;31:2744-2754) (C) 2009 Excerpta Medica Inc.