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  • 學位論文

家兔體內丙酮酸對 sulfadiazinne 藥物動力學之影響

Influence of pyruvic acid on the pharmacokinetics of sulfadiazine in rabbits

指導教授 : 許光陽
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摘要


遺傳多型影響藥物代謝已經證實,其中乙醯化遺傳多型之研究又多以乙醯 轉化有關。然而,先前研究曾指出,不同表現型家兔之內生丙酮酸濃度有 明顯不同,並且藥物乙醯化亦與丙酮酸抱合代謝之間具有消長關係,因此 懷疑丙酮酸之代謝與乙醯藥物之間有否關聯。故本研究之目的在於瞭解家 兔體內丙酮酸(PA)之變化,並探討丙酮酸對Sulfadiazine(SDZ)藥物動力 學之影響。以SDZ為標的藥物,檢測家兔之乙醯化表現型,共計26隻雄性 紐西蘭家兔,其中慢速乙醯化型12隻,快速乙醯化型14隻,經靜脈投予不 同劑量之 PA,在100 mg/kg∼200 mg/kg的範圍中,家兔體內PA的代謝情 形為一dose -independent的現象,其AUC與劑量之間呈線性關係(0至無限 時間,Y= 21.570X-535.508,r squre=0.9396;0至40分鐘,Y=12.275 X-518.391,r squre=0.9997)。且不同表現型家兔所得之各動力學參數, 統計學上並無差異(P>0.05)。顯示PA在兩種乙醯表現型之體內變化並無不 同。又以靜脈連續輸注的方式投予PA,將PA維持在一定恆定之高濃度100 microgram/ml下,再投與SDZ,探討PA對於SDZ之影響。其結果以ANOVA分 別檢定慢速及快速乙醯化型家兔之SDZ藥物動力學之各項參數間的變異。 結果顯示快速乙醯化型兔子不受高濃度PA之影響(p>0.05)。但在慢速乙醯 化型家兔,在beta-half life顯示有意義差異(p<0.01),由105.90 .plusmi. 6.53 min降為61.52 .plusmi. 13.81 min,明顯的加速排泄。由 此在相同之高濃度下,PA對於乙醯多型有不同之作用。其可能之原因為藥 物乙醯化之加快及產生丙酮酸抱合代謝。

關鍵字

遺傳多型 乙醯化 表現型 丙酮酸

並列摘要


Polymorphism is an important factor that affect the metabolism of drugs. Mechanism of acetylation polymorphism is more certain in recent decade. Acetylation phenotype of rabbits were deter- mined by using sulfadiazine as an indicating drug, and there were twelve slow acetylation rabbits and fourteen rapid acetylation rabbits used in this experiments. After different dose admini- stration of pyruvic acid(100 mg/kg to 200 mg/kg), elimination of pyruvic acid represent a dose independence in rabbits. AUC( area under curve) is proportional to various dose( time:from 0 to infinite, Y=21.570X-535.508,r squre=0.9396;time from 0 to 40, Y =12.275X-518.391,r squre=0.9997). There were no significant di- fference between acetylation phenotype and the elimination of pyruvic acid.(p>0.05) Maintaining 100 microgram/ ml plasma concentration of pyruvic acid by I.V. infusion to rabbits, the influences of pyruvic acid to the elimination of sulfadiazine were evaluted. ANOVA was used to analysis the differences of pharmacokinetic parameters of sulfadiazine between control ans pyruvic acid infused rabbits. On rapid acetylators, there were no significant differences in all pharmacokinetic parameters.(p>0.05) On the other way, di- fference of beta-half life in slow acetylators were obtained. (p<0.01) Beta-half life were 105.90 .plusmi. 36.53 minutes in control and 61.52 .plusmi. 13.81 minutes in pyruvic acid infused. The reason of influence of pyruvic acid on slow acetylation rabbits may be pyruvic acid enhance the acetylation of sulfadiazine or the conjugation of pyruvic acid and sulfadiazine.

並列關鍵字

polymorphism acetylation phenotype pyruvic acid sulfadiazine

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