Diphenidol於台灣志願者之藥物動力學研究

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標題:	Diphenidol於台灣志願者之藥物動力學研究 The Pharmacokinetics of Diphenidol in Taiwanese subjects
作者:	沈碧瑩 Pi-ying Shen
貢獻者:	宋國峻嘉南藥理科技大學：藥物科技研究所
關鍵字:	線性藥物動力學藥物動力學 linear pharmacokinetics pharmacokinetics Diphenidol
日期:	2007
上傳時間:	2010-06-01 09:21:32 (UTC+8)
摘要:	Diphenidol常用於因內耳障礙引起之眩暈，嘔吐、眼振、美尼爾氏疾病的治療，有強烈的鎮吐作用。Diphenidol 中毒時可能引起的症狀，主要以抗乙醯膽鹼作用為主，可產生擴瞳、心搏加速、躁動、神智昏亂、幻覺、抽搐、昏迷、皮膚乾燥、顏面潮紅、腸胃蠕動減慢等症狀。由於 Diphenidol於台灣臨床之使用尚無其體內藥動學相關文獻報告，為避免引起嚴重毒性，提供臨床合理用藥依據，因此本研究目的乃在於建立 Diphenidol於台灣健康志願者之體內動力學參數，並研究口服三種不同劑量之 Diphenidol於人體藥動學，同時探討其藥物動力學參數和劑量間是否存在的線性之變化模式。方法十二名健康志願者隨機分成三組，以單一劑量口服方式，服用25mg、50mg及75mg 之Diphenidol以評估線性藥動學模式。另外有十二個志願者以單一劑量口服方式，服用25mg之Diphenidol。探討Diphenidol於台灣健康志願者之體內動力學參數變化，二者之血液樣品收集時間直到36小時，以LC/MS/MS來檢測血中藥物濃度，求得藥物動力學參數。結果十二位志願者以單一口服方式服用三種不同劑量之Diphenidol，其排除半衰期（t1/2）分別各為5.95±3.23hr、6.29±0.3hr、7.36±3.06hr，經統計結果顯示其值並未因劑量增加而有所不同。將三個劑量所得之AUC及Cmax和劑量間做相關性的研究後，結果亦顯示此二參數均隨著劑量的增大呈線性增加，且劑量之高低與Tmax值大小並無顯著差異。另外在建立體內動力學參數部分，十二位志願者以口服方式服用單一劑量25mg Diphenidol後，其AUC0~t 為562 ± 270 hrng/ml，Tmax 介於1.0和4 hr間，與國外文獻記載之數據1.5~3 hr相似。排除半衰期為6.29±2.16hr，此文獻記載約4 hr稍長，也比Jos´e Herna´ndez.的研究報告上排除半衰期 3hr長約2倍。結論由本研究結果所得Diphenidol於血中藥物濃度與口服藥物量呈線性動力學模式，因此在此線性範圍下，可根據劑量的變化來推算血中藥物濃度的改變程度。而本研究所得在台灣健康志願者所呈現之各項動力學參數數據，則可提供各臨床應用上之參考依據。 Background and Purpose: Diphenidol is an antiemtic agent in treatment of vomiting and vertigo. It has been reported to cause various adverse effects including hallucination, confusion and occasionally drowsiness. Since there was limited pharmacokinetic data of Diphenidol in the pervious literature, the purpose of our studies is to examine the pharmacokinetics of Diphenidol in Taiwanese subjects. Methods: The relatiship between dose and pharmacokinetic parameter of Diphenidol was assessed in tweleve healthy Taiwanese after administration of single oral dose of 25, 50 and 75mg. A randomized balanced, parallel design was used. Moreover, in order to obtain pharmacokinetic parameters of Diphenidol in Taiwanese subjects, twelve healthy adult Taiwanese were randomized to receive a single dose of Diphenidol (25mg). Serial blood samples were taken up to 36 hr post-dose and plasma concentrations of Diphendol were determined by using LC/MS/MS. Results: The linear pharmacokinetics behavior of Diphenidol was observed following oral administration of 25, 50, and 75 mg Diphenidol in Taiwanese subjects. The mean elimination half-life (t1/2) of Diphenidol were 5.95 ± 3.23, 6.29 ± 0.30 and 7.36 ± 3.06 hr for those doses, respectively. The peak plasma levels (Cmax) and the concentration-time curves (AUCs) data also showed dose-proportional response. The time to peak plasma concentration (Tmax) was similar regardless of the administered dose. Following oral administration of 25mg Diphenidol in tweleve Taiwanese subjects, the AUC0-∞ were 562 ± 270 hrng/ml and the Tmax were between 1 hr to 4 hr. The mean elimination half-life (t1/2) of Diphenidol were 6.29 ± 2.16 hr, which were higher than compared to the results obtained from Mexican population. Conclusions: These findings suggest that the pharmacokinetic behavior of Diphenidol is linear over the dose range studied. Pharmacokinetic parameters of Diphenidol obtained in the present study can be utilized as reference for various clinical applications.
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