"2-胺基-3-甲基咪唑[4,5-f]喹啉在大鼠體內藥物動力學之探討"

Abstract

異環胺為一種高蛋白肉品高溫烹煮後所產生之致癌性化合物，在國人的飲食中皆有暴露的可能，進而對民眾造成致癌風險，為了保障民眾食的安全的必須建構一個客觀的風險評估，因此本研究利用動物模式求得異環胺中2-胺基-3-甲基咪唑[4,5-f]喹啉在大鼠體內的藥物動力學參數，進而了解大鼠在暴露2-胺基-3-甲基咪唑[4,5-f]喹啉後在體內的代謝情形以作為後續風險評估上的運用。而回述相關文獻，目前國際上未有異環胺藥物動力學的相關研究，因此本實驗選擇在眾多異環胺中在IRAC中被歸類為group 2A之2-胺基-3-甲基咪唑[4,5-f]喹啉當作本次實驗的研究物質。 本研究之目的為利用高效液相層析串聯質譜儀建立2-胺基-3-甲基咪唑[4,5-f]喹啉於大鼠血液中的偵測方法，並利用此分析方法，在大鼠動物模式的架構下，探討2-胺基-3-甲基咪唑[4,5-f]喹啉之藥物動力學並比較藥物動力學在公母鼠性別中的差異。本研究符合美國食品藥物管理局的建議規範，方法確效包括了線性、精確性、準確性、基質效應、萃取回收率、以及安定性的評估。 實驗結果顯示公母大鼠靜脈給予10 mg/kg以及口胃給予5 mg/kg、10 mg/kg，其中所得到公鼠平均半衰期分別為117.9 ± 49.7、77.98 ± 9.84、118.1 ± 76.5分鐘；母鼠平均半衰期分別為66.73 ± 28.9、157.5 ± 99.9、129.8 ± 68.0分鐘。此外2-胺基-3-甲基咪唑[4,5-f]喹啉在公鼠口胃給予5 mg/kg、10 mg/kg的劑量下之平均口服生體可用率分別為29.36 ± 6.80、27.2 ± 9.1 ％；而在母鼠的中的平均口服生體可用率分別為6.43 ± 2.66、13.26 ± 3.41 ％。 研究結果發現，由於2-胺基-3-甲基咪唑[4,5-f]喹啉之親水性在吸收後傾向分布細胞外液，而在公鼠的廓清率較母鼠來的高，在公鼠口胃給予5和10 mg/kg之間有線性藥物動力學關係；母鼠則在口胃給予5和10 mg/kg劑量之間呈現非線性藥物動力學的現象。暴露2-胺基-3-甲基咪唑[4,5-f]喹啉後在公鼠體內有較高的生體可用率，推斷原因是公母鼠肝臟P450細胞色素中的CYP1A2酵素活性差異所致。希望此研究成果能作為後續風險評估之參考依據。

Heterocyclic amines (HCAs) are potent carcinogens to which humans are frequently exposed through the consumption of cooked meat and fish food. Thus, a risk assessment needs to be established to minimize the cancer risk. This study used animal model to obtain and understand the pharmacokinetics of 2-Amino-3-methyl-3H-imidazo[4,5-f] quinolone in rats and apply that to risk assessment. Nevertheless, the pharmacokinetic studies of 2-Amino-3-methyl-3H-imidazo[4,5-f] quinolone have not been fully investigated. Thus, this study chose 2-Amino-3-methyl-3H-imidazo[4,5-f] quinolone (IQ), classified as Group 2A in IARC, in our study. The aim of the study is to develop a high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method to determine 2-Amino-3-methyl-3Himidazo[4,5-f] quinolone and discuss the difference of pharmacokinetic between male and female rats. Method validation, including linearity, accuracy, precision, matrix effect, recovery, and stability, is recommended by the U.S. Food and Drug Administration (US-FDA). The result indicated that after the administration of IQ in male rats, the average elimination half-lives of one intravenous (10mg/kg) and two oral dose (5mg/kg and 10mg/kg) are 117.9 ± 49.7, 77.98 ± 9.84 and 118.1 ± 76.5 min, respectively; the average elimination half-lives of one intravenous (10mg/kg) and two oral dose (5mg/kg and 10mg/kg) in female are 66.73 ± 28.9, 157.5 ± 99.9 and 129.8 ± 68.0 min,respectively. Besides, the oral bioavailability of two oral dose (5mg/kg and 10mg/kg) in male rats are 29.36 ± 6.80 % and 27.2 ± 9.1 %;the oral bioavailability of two oral dose (5mg/kg and 10mg/kg) in female rats are 6.43 ± 2.66 and 13.26 ± 3.41 ％. Our finding reveals that IQ tends to distribute in extracellular fluid. The clearance rate in male rats is higher than female rats. Linear pharmacokinetics are found between two oral dose (5mg/kg and 10mg/kg) in male rats; nonlinear pharmacokinetics are found between two oral dose (5mg/kg and 10mg/kg) in female rats. We speculate that the difference of activity of CYP1A2 enzyme in the liver of rats is the main reason to cause the oral bioavailability in male rats are higher than in female rats. Our finding will help to determine the further studies of risk assessment.