CIR and Drug Sciences, University Campus Bio-Medico, Via Alvaro del Portillo 21, 00128 Rome, Italy.
Drug Metab Dispos. 2012 Dec;40(12):2365-73. doi: 10.1124/dmd.112.047480. Epub 2012 Sep 12.
The pharmacokinetics of pegylated liposomal doxorubicin (PLD) were investigated in 17 women undergoing intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian cancer and peritoneal carcinomatosis. HIPEC was performed immediately after completing debulking surgery, which included a number of peritonectomy procedures. PLD was injected and allowed to equilibrate in peritoneal cavity filled with 4 liters of physiological solution and stabilized at 42°C; next, the outflow line was opened and perfusion proceeded for 1 h. PLD was stable in peritoneal perfusate and plasma. During HIPEC, PLD peritoneal perfusate/plasma gradients averaged ∼600 or ≥1000 for peak concentration or area under the curve. After HIPEC, PLD plasma levels remained stable or decreased. Biopsy samples of residual normal peritoneum or ovarian carcinomatosis were collected at the end of HIPEC and were shown to contain free doxorubicin. Correlating PLD decrements in peritoneal perfusate with plasma exposure to PLD or peritoneal deposition of free doxorubicin showed that the former occurred during preperfusional equilibration of PLD in peritoneal cavity, whereas the latter occurred during 1 h of perfusion. Plasma exposure to PLD correlated negatively with the number of peritonectomy procedures performed during surgery, whereas peritoneal deposition of free doxorubicin correlated positively. Taken together, these results show that PLD administered by intraoperative HIPEC undergoes limited systemic diffusion and releases active free doxorubicin in peritoneum exposed to ovarian carcinomatosis. PLD pharmacokinetics seem to be influenced by peritonectomy procedures.
聚乙二醇脂质体阿霉素（PLD）的药代动力学在 17 名接受晚期卵巢癌和腹膜癌性转移术中腹腔内热灌注化疗（HIPEC）的女性中进行了研究。HIPEC 在完成肿瘤减灭术（包括多次腹膜切除术）后立即进行。PLD 被注入并在充满 4 升生理溶液的腹腔中平衡，同时将温度稳定在 42°C；然后，打开流出管路并进行 1 小时的灌注。PLD 在腹腔灌洗液和血浆中稳定。在 HIPEC 过程中，PLD 腹腔灌洗液/血浆浓度梯度平均为 600 倍或 1000 倍以上，达到峰值浓度或曲线下面积。HIPEC 后，PLD 血浆水平保持稳定或下降。HIPEC 结束时收集残余正常腹膜或卵巢癌性转移组织的活检样本，结果显示含有游离阿霉素。将 PLD 腹腔灌洗液中的递减与 PLD 的血浆暴露或游离阿霉素的腹腔沉积与 PLD 递减进行相关分析，结果表明前者发生在 PLD 在腹腔中的预灌注平衡期间，而后者发生在 1 小时的灌注期间。PLD 的血浆暴露与手术期间进行的腹膜切除术数量呈负相关，而游离阿霉素的腹腔沉积与腹膜切除术数量呈正相关。综上所述，这些结果表明，术中 HIPEC 给予的 PLD 经历了有限的全身扩散，并在暴露于卵巢癌性转移的腹膜中释放出活性游离阿霉素。PLD 的药代动力学似乎受腹膜切除术的影响。
