模拟低氧环境对对乙酰氨基酚药动学的影响
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摘要
目的研究对乙酰氨基酚在模拟低氧条件下药代动力学特征的变化,为其在高原环境下的临床应用提供理论依据。方法将SD大鼠分为平原组(常氧条件饲养)、急性缺氧组(低压氧舱连续饲养4 d)和慢性缺氧组(低压氧舱连续饲养30 d) 3组。大鼠灌胃给药后,在10 min及0. 5、1、1. 5、2、3、4、6、8、12 h时于眼底静脉取血,采用HPLC法测定血浆中对乙酰氨基酚的浓度,计算药动学参数。结果与平原组大鼠相比,急性低氧组和慢性低氧组的t_(1/2)、MRT、AUC、C_(max)增加,CL、Vd、ke减小。结论在低氧环境中,对乙酰氨基酚的代谢减慢。
OBJECTIVE To study the changes of pharmacokinetic characteristics of Acetaminophen under simulated hypoxia,and to provide the theoretical basis for its clinical application in high altitude environment. METHODS SD rats were divided into three groups: plain group( feeding under normoxic conditions),acute hypoxia group( low-pressure oxygen chamber continuous feeding for 4 days) and chronic hypoxia group( low-pressure oxygen chamber continuous feeding for 30 days). After oral administration in rats,the plasma concentration of Acetaminophen was determined by HPLC,and the pharmacokinetic parameters were calculated. RESULTS Compared with the plain group,the t_(1/2),MRT,AUC,and C_(max) of the acute hypoxic group and the chronic hypoxic group were increased,CL,V_d,and kewere reduced. CONCLUSION The metabolism of Acetaminophen is slowed down in a hypoxic environment.
OBJECTIVE To study the changes of pharmacokinetic characteristics of Acetaminophen under simulated hypoxia,and to provide the theoretical basis for its clinical application in high altitude environment. METHODS SD rats were divided into three groups: plain group( feeding under normoxic conditions),acute hypoxia group( low-pressure oxygen chamber continuous feeding for 4 days) and chronic hypoxia group( low-pressure oxygen chamber continuous feeding for 30 days). After oral administration in rats,the plasma concentration of Acetaminophen was determined by HPLC,and the pharmacokinetic parameters were calculated. RESULTS Compared with the plain group,the t_(1/2),MRT,AUC,and C_(max) of the acute hypoxic group and the chronic hypoxic group were increased,CL,V_d,and kewere reduced. CONCLUSION The metabolism of Acetaminophen is slowed down in a hypoxic environment.
引文
[1]Hurtado A,Escudero E,Pando J,et al.Cardiovascular and renal effects of chronic exposure to high altitude[J].Nephrol Dial Transplant,2012,27(suppl 4):11-16.
[2]Yamaji R,Sakamoto M,Miyatake K,et al.Hypoxia inhibits gastric emptying and gastric acid secretion in conscious rats[J].J Nutr,1996,126(3):673-680.
[3]Aronwisnewsky J,Minville C,Tordjman J,et al.Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese[J].J Hepatology,2012,56(1):225-233.
[4]Adak A,Maity C,Ghosh K,et al.Alteration of predominant gastrointestinal flora and oxidative damage of large intestine under simulated hypobaric hypoxia[J].Zeitschrift Für Gastroenterologie,2014,52(2):180-186.
[5]李向阳,刘永年,李永平,等.磺胺甲噁唑在平原汉族、高原世居汉族和藏族健康人体的药物代谢动力学研究[J].药学学报,2011,46(9):1117-1122.
[6]Jr WT.Cardiovascular Medicine at High Altitude[J].Angiology,2014,65(6):459-472.
[7]郭凤霞,徐晓玲,李锦萍,等.高海拔下低氧对高原鼠兔氧解离曲线关键因子的影响[J].华西药学杂志,2016,31(5):475-476.
[8]张娟玲,李向阳.高原低氧影响药物代谢的研究进展[J].药学学报,2015,50(9):1073-1079.
[9]Zhou XJ,Nian YQ,Li XY,et al.Hypoxia plays a key role in the pharmacokinetic changes of drugs at high altitnde[J].Cur Drug Metab,2018,19(11):960-969.
[10]Zhang J,Zhu J,Yao X,et al.Pharmacokinetics of lidocaine hydrochloride metabolized by CYP3A4 in Chinese Han volunteers living at low altitude and in native Han and Tibetan Chinese volunteers living at high altitude[J].Pharmacology,2016,97(3-4):107-113.
[11]Li XY,Gao F,Li ZQ,et al.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[J].Clin Ther,2009,31(11):2744-2754.
[12]Arancibia A,Paulos C,Chávez J,et al.Pharmacokinetics of lithium in healthy volunteers after exposure to high altitude[J].Int J Clin Pharmacol Ther,2003,41(5):200-206.
[13]李文斌,贾正平,谢华,等.急进高原对普萘洛尔药代动力学参数的影响[J].中南大学学报:医学版,2013,38(9):909-914.
[14]张娟红,王荣,谢华,等.急进高原对普萘洛尔和美托洛尔在大鼠体内药代动力学的影响[J].J South Med Univ,2014,34(11):1616-1620.
[15]Gola S.Hepatic metabolism of ibuprofen in rats under acute hypobaric hypoxia[J].Exp Toxicol Pathol,2013,65(6):751-758.
[16]Gola S,Gupta A,Keshri GK,et al.Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude[J].J Pharm Biomed Anal,2016,121:114-122.
[17]Bhushan B,Walesky C,Manley M,et al.Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model[J].American J Pathology,2014,184(11):3013-3025.
[18]Mattia A,Coluzzi F.What anesthesiologists should know about paracetamol(acetaminophen)[J].Minerva Anestesiol,2009,75(11):644-53.
[19]汪倩,徐瑞娟,杨劲.对乙酰氨基酚肝毒性机理及药物干预靶点[J].药学与临床研究,2011,19(3):247-252.
[20]倪倩.高原习服中大鼠肝脏葡萄糖、脂肪酸代谢特点及机制[D].兰州:兰州大学硕士学位论文,2014.
[21]Qinna NA,Shubbar MH,Matalka KZ,et al.Glucosamine enhances paracetamol bioavailability by reducing its metabolism[J].J Pharmaceutical Sci,2015,104(1):257-265.
[2]Yamaji R,Sakamoto M,Miyatake K,et al.Hypoxia inhibits gastric emptying and gastric acid secretion in conscious rats[J].J Nutr,1996,126(3):673-680.
[3]Aronwisnewsky J,Minville C,Tordjman J,et al.Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese[J].J Hepatology,2012,56(1):225-233.
[4]Adak A,Maity C,Ghosh K,et al.Alteration of predominant gastrointestinal flora and oxidative damage of large intestine under simulated hypobaric hypoxia[J].Zeitschrift Für Gastroenterologie,2014,52(2):180-186.
[5]李向阳,刘永年,李永平,等.磺胺甲噁唑在平原汉族、高原世居汉族和藏族健康人体的药物代谢动力学研究[J].药学学报,2011,46(9):1117-1122.
[6]Jr WT.Cardiovascular Medicine at High Altitude[J].Angiology,2014,65(6):459-472.
[7]郭凤霞,徐晓玲,李锦萍,等.高海拔下低氧对高原鼠兔氧解离曲线关键因子的影响[J].华西药学杂志,2016,31(5):475-476.
[8]张娟玲,李向阳.高原低氧影响药物代谢的研究进展[J].药学学报,2015,50(9):1073-1079.
[9]Zhou XJ,Nian YQ,Li XY,et al.Hypoxia plays a key role in the pharmacokinetic changes of drugs at high altitnde[J].Cur Drug Metab,2018,19(11):960-969.
[10]Zhang J,Zhu J,Yao X,et al.Pharmacokinetics of lidocaine hydrochloride metabolized by CYP3A4 in Chinese Han volunteers living at low altitude and in native Han and Tibetan Chinese volunteers living at high altitude[J].Pharmacology,2016,97(3-4):107-113.
[11]Li XY,Gao F,Li ZQ,et al.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[J].Clin Ther,2009,31(11):2744-2754.
[12]Arancibia A,Paulos C,Chávez J,et al.Pharmacokinetics of lithium in healthy volunteers after exposure to high altitude[J].Int J Clin Pharmacol Ther,2003,41(5):200-206.
[13]李文斌,贾正平,谢华,等.急进高原对普萘洛尔药代动力学参数的影响[J].中南大学学报:医学版,2013,38(9):909-914.
[14]张娟红,王荣,谢华,等.急进高原对普萘洛尔和美托洛尔在大鼠体内药代动力学的影响[J].J South Med Univ,2014,34(11):1616-1620.
[15]Gola S.Hepatic metabolism of ibuprofen in rats under acute hypobaric hypoxia[J].Exp Toxicol Pathol,2013,65(6):751-758.
[16]Gola S,Gupta A,Keshri GK,et al.Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude[J].J Pharm Biomed Anal,2016,121:114-122.
[17]Bhushan B,Walesky C,Manley M,et al.Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model[J].American J Pathology,2014,184(11):3013-3025.
[18]Mattia A,Coluzzi F.What anesthesiologists should know about paracetamol(acetaminophen)[J].Minerva Anestesiol,2009,75(11):644-53.
[19]汪倩,徐瑞娟,杨劲.对乙酰氨基酚肝毒性机理及药物干预靶点[J].药学与临床研究,2011,19(3):247-252.
[20]倪倩.高原习服中大鼠肝脏葡萄糖、脂肪酸代谢特点及机制[D].兰州:兰州大学硕士学位论文,2014.
[21]Qinna NA,Shubbar MH,Matalka KZ,et al.Glucosamine enhances paracetamol bioavailability by reducing its metabolism[J].J Pharmaceutical Sci,2015,104(1):257-265.