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
中文摘要
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。
英文摘要
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.
