PBA-ω-Lys 做為緩釋 phenylbutyric acid 型前驅藥的藥物動力學研究   全文下載

PBA-ω-Lys as Sustained Phenylbutyrate-Releasing Prodrug

癌症化學療法或放射線療法常導致嚴重的粘膜潰瘍。組蛋白去乙醯脢抑制劑（HDACi）被發現具有抑制發炎反應，其中phenylbutyric acid （PBA）鈉鹽被證實對化學療法產生之粘膜潰瘍具有癒合效果,唯其活性不高，且限於局部使用，做為癌症治療輔助劑不具競爭力。基於發炎組織的陰電性病理環境，本研究以PBA為基底，利用帶有正電荷且對身體友善的氨基酸Lysine與PBA鍵結，形成標靶型前驅藥，以帶正電之Lysine導引PBA聚焦至發炎組織，以系統性給藥取代區域給藥，做為粘膜潰瘍傷口之癒合劑。本研究合成PBA-α-Lys及PBA-ω-Lys二個前驅藥，與原藥PBA分別口服及靜脈注射至大鼠，再以高效能液相層析儀分析血液樣本，運用WinNonlin之非室模式計算前驅藥與原藥之動力學，計算其生體可用率。口服PBA-α-Lys或PBA-ω-Lys後得到的PBA生體可用率均比靜脈注射高，顯示肝臟首渡效應是釋放PBA的主要機制。口服PBA-α-Lys後該前驅藥之生體可用率不高（3.5%），其動力學參數與口服PBA鈉鹽之動力學參數相近，由於PBA-α-Lys在人工腸液之穩定性欠佳，推測該前驅藥在小腸快速代謝，再以原藥吸收，顯示其並非一個理想的PBA前驅藥。口服PBA-ω-Lys之生體可用率亦不高（1.8%），但在體內釋出PBA之可用率高於以PBA sodium原型給藥（AUMCinf 168.7 ± 67.7 hr*hr*μg/mL vs 88.8 ± 12.4 hr*hr*μg/mL）。口服PBA-ω-Lys呈現緩釋PBA之動力學，值得進一步研究其聚焦至發炎粘膜組織之藥物動力學以及其抗發炎與傷口癒合效果。"

Lysine was attached to phenylbutyric acid (PBA) to form PBA-α-Lys and PBA-ω-Lys as PBA prodrugs for treating chemo-therapy-associated mucositis. Pharmacokinetic studies were conducted in Wistar rats for determining the systemic bioavail-ability of both prodrugs and the released PBA. The systemic bioavailability of PBA after oral administration of PBA-α-Lys or PBA-ω-Lys was higher than from i.v. administration, indicating that first pass effect is responsible for the transformation from the prodrugs to the parent drug. Lack of stability in the intestine made PBA-α-Lys unsatisfied as an oral prodrug of PBA. Oral admin-istration of PBA-ω-Lys, on the other hand, led to a slow PBA-releasing profile in circulation. Although the AUC0→t of systemic released PBA from oral administration of PBA-ω-Lys was lower than from oral administration of PBA per se, MRTinf was 5 times longer (9.64 ± 2.16 vs 1.81 ± 0.28 hr), t1/2 was 4 times longer (6.18 ± 2.09 hr vs 1.50 ± 0.17 hr), and AUMCinf was 2 folds higher (168.7 ± 67.7 hr*hr*μg/mL vs 88.8 ± 12.4 hr*hr*μg/mL). In conclusion, oral administration of PBA-ω-Lysine exhibited a sustained PBA-releasing pharmacokinetic profile in rats. The bioavailability of PBA released in inflammatory tissues and anti-mucositis activity need to be further investigated for the evaluation of PBA-ω-Lysine as an effective targetable anti-mucositis agent.