Nalbuphine是一種半合成鴉片類藥物，其適應症為緩解中度至重度疼痛。Nalbuphine的藥動半衰期很短，臨床上需要提高注射頻率來維持藥效，但此方式所造成的大範圍血液濃度差異卻提高藥物不良反應的發生率。 Dinalbuphine sebacate，為nalbuphine的前驅藥，其化學結構為兩個nalbuphine中間利用酯鍵連結形成一個dinalbuphine sebacate，是一種油性緩釋止痛注射劑。 由於代謝對藥物的功效和安全性有顯著的影響，我們使用人類肝臟微粒體來評估dinalbuphine sebacate的生物轉化，以確定其體外藥物代謝的情形。 酯解酶對於前驅藥的活化是必需的。 因此，我們分析了大鼠血液、肌肉和肝臟組織中的dinalbuphine sebacate水解率，以比較在不同組織中酯解酶對dinalbuphine sebacate的催化活性。 在之前dinalbuphine sebacate的試驗研究中，nalbuphine是唯一可測量到的代謝產物；而血漿中的dinalbuphine sebacate濃度則是低於最低偵測極限。 我們推測造成dinalbuphine sebacate濃度過低的可能原因有兩個，一是dinalbuphine sebacate之水解現象而另一個則是dinalbuphine sebacate的親脂性。 由於dinalbuphine sebacate相對疏水，其在血漿和紅血球之間的分配現象尚不清楚。 因此，我們執行了在人類全血中，nalbuphine與dinalbuphine sebacate對於血漿與紅血球的分配相關性研究，以求得nalbuphine與dinalbuphine sebacate在人類血液中的分配係數。 由於我們進行了一系列dinalbuphine sebacate的體外代謝研究，更加了解其體外代謝的概況。 基於這些體外代謝的研究結果，評估dinalbuphine sebacate油針劑型在人體內的生體可用率值得一試，並且可進一步探討dinalbuphine sebacate油針劑型是否比nalbuphine注射液在人體內能持續更長時間的血液nalbuphine有效濃度。
我們在健康受試者中進行了dinalbuphine sebacate生體可用率的臨床研究，以驗證此緩釋劑型能延長nalbuphine的血液濃度分佈。 此試驗在健康受試者分別進行肌肉內注射nalbuphine注射液和dinalbuphine sebacate油針劑型，之後比較此兩種劑型的藥物動力學差異。 十二名健康的台灣人隨機接受20毫克nalbuphine和150毫克的dinalbuphine sebacate，中間經過連續5天的沖洗期。 在樣品分析過程中，為了防止酯鍵水解，我們評估了四種酯解酶抑制劑在dinalbuphine sebacate定量實驗中的抑制效果。 研究結果為噻吩甲酰基三氟丙酮（TTFA）的抑制效果最佳，並將其應用於兩種驗證過的液相層析串聯式質譜分析方法，分別在人類全血中測定nalbuphine和dinalbuphine sebacate的濃度。 將分別注射nalbuphine注射液和dinalbuphine sebacate油針劑型後所測得的受試者血液中nalbuphine濃度相比，dinalbuphine sebacate油針劑型具有85.4 % 的生體可用率。 Dinalbuphine sebacate油針劑型的平均吸收時間為145.2小時。 Dinalbuphine sebacate油針劑型將nalbuphine完全釋放到血液中大約需要六天的時間，進入血液後，dinalbuphine sebacate因酯解酶作用迅速水解成nalbuphine。 本研究指出單次注射150毫克的dinalbuphine sebacate長效止痛劑型可以提供為期一週的疼痛緩解。

Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Its short half-life requires frequent injections in clinical practices, which results in greater incidences of adverse events due to a wide range of peak and trough blood concentrations. We have developed dinalbuphine sebacate (DNS), a synthetic prodrug with two active nalbuphine moieties joined with a sebacoyl ester, dissolved in a simple oil-based injectable formulation. Since drug metabolism has a significant effect on its efficacy and safety, we evaluate biotransformation of DNS using human liver microsomes to determine its in vitro drug metabolism. In general, enzymes are essential for prodrug activation. We analyzed DNS hydrolysis rate in rat blood, muscle and liver to compare catalytic activity of esterases on DNS, our ester-based prodrug, in different tissues. In the previous study, nalbuphine was the only measurable metabolic product while plasma concentrations of DNS were below the low quantitation limit. We speculated DNS hydrolysis issues and its lipophilicity as the possible reasons for lower plasma concentrations. Since DNS was relatively hydrophobic, its partition between plasma and red blood cells in whole blood was still unknown. Therefore, we conducted the partition coefficient study of nalbuphine and DNS in human whole blood to evaluate their partition between human plasma and red blood cells. To prevent DNS hydrolysis during sample analysis, we evaluated four esterase inhibitors in the quantitation of DNS. Because we performed a series of in vitro metabolism studies of DNS, we got more clear profiles. It is worthy to evaluate bioavailability of DNS in oil solution based on our in vitro hydrolysis results and to see if it could maintain effective blood nalbuphine level for longer duration in human than nalbuphine aqueous injection.
An open-label, prospective, two-period study was performed in healthy volunteers to verify the extended blood concentration profile of nalbuphine. Pharmacokinetics of intramuscularly administered DNS was compared with that of nalbuphine HCL injection in healthy volunteers. Twelve healthy Taiwanese were randomized to receive intramuscular injection of 20 mg nalbuphine HCL and 150 mg DNS sequentially with a washout period of 5 days. Thenoyltrifluoroacetone (TTFA) was chosen for two validated LC-MS/MS methods; quantifying nalbuphine and DNS in human whole blood, respectively. The bioavailability of nalbuphine from intramuscularly injected DNS relative to that from nalbuphine HCL was 85.4%. The mean absorption time of nalbuphine from DNS was 145.2 hr. It took approximately 6 days for complete release of DNS into blood stream where DNS was rapidly hydrolyzed to nalbuphine; suggesting a single injection of 150 mg DNS in our extended-release formulation could provide a week-long pain relief.

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