Triesscheijn Martijn, Ruevekamp Marjan, Out Ruud, Van Berkel Theo J C, Schellens Jan, Baas Paul, Stewart Fiona A
Division of Experimental Therapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2007 Jun;60(1):113-22. doi: 10.1007/s00280-006-0356-9. Epub 2006 Sep 29.
Meso-tetra-hydroxyphenyl-chlorin (mTHPC) is a hydrophobic photosensitizer that binds to plasma lipoproteins after intravenous injection. In vitro experiments with human plasma have shown that mTHPC initially binds to an unknown protein and subsequently redistributes to lipoprotein fractions. It has been suggested that this might explain the unusual pharmacokinetic profile of mTHPC humans. In humans, unlike in rodents, reappearance of mTHPC has been reported, resulting in a second plasma peak after intravenous injection. However, previous studies analyzed only limited time points during the first 24 h after injection. Our aim was to determine the pharmacokinetics of mTHPC in detail, and to investigate whether the pharmacokinetic behavior of the drug is affected by binding of mTHPC to lipoproteins in vivo.
Plasma of cancer patients and mice, intravenously injected with mTHPC, was analyzed for total drug content and drug distribution over the lipoprotein fractions.
Pharmacokinetic profiles of mTHPC in a group of human subjects showed that apparent steady state drug levels were maintained for at least 10 h. Closer examination of individual profiles showed that the initial (5 min) plasma drug levels were on average 86% of the maximal plasma concentration, which occurred at about 5 h after injection. In mice, however, plasma pharmacokinetics were described by a standard bi-exponential decline of the drug concentration. The majority (>58%) of mTHPC injected into both BALB/c nude mice and patients initially bound to the HDL plasma fraction. We extended our study to ApoE -/- mice, with highly elevated lipoprotein levels, and SR-BI -/- mice, which are lacking the main clearance pathway for HDL associated cholesteryl esters, to take into account the differences between lipoprotein levels and clearance in mice and man. Although mTHPC distribution over the lipoproteins changed in these mice, pharmacokinetic profiles of mTHPC remained the same.
We conclude that neither lipoprotein levels nor cholesterol metabolism affects the pharmacokinetics of mTHPC in plasma.
中-四-羟基苯基-二氢卟吩（mTHPC）是一种疏水性光敏剂，静脉注射后可与血浆脂蛋白结合。用人血浆进行的体外实验表明，mTHPC最初与一种未知蛋白质结合，随后重新分布到脂蛋白组分中。有人认为，这可能解释了mTHPC在人体中不寻常的药代动力学特征。与啮齿动物不同，在人体中，有报道称mTHPC会再次出现，导致静脉注射后出现第二个血浆峰。然而，之前的研究仅分析了注射后最初24小时内的有限时间点。我们的目的是详细确定mTHPC的药代动力学，并研究该药物的药代动力学行为是否受mTHPC在体内与脂蛋白结合的影响。
对静脉注射mTHPC的癌症患者和小鼠的血浆进行分析，以测定总药物含量和药物在脂蛋白组分中的分布。
一组人类受试者中mTHPC的药代动力学曲线表明，明显的稳态药物水平至少维持了10小时。对个体曲线的进一步检查表明，初始（5分钟）血浆药物水平平均为最大血浆浓度的86%，最大血浆浓度出现在注射后约5小时。然而，在小鼠中，血浆药代动力学表现为药物浓度的标准双指数下降。注入BALB/c裸鼠和患者体内的mTHPC，大部分（>58%）最初与高密度脂蛋白（HDL）血浆组分结合。考虑到小鼠和人类脂蛋白水平及清除率的差异，我们将研究扩展到脂蛋白水平高度升高的载脂蛋白E基因敲除（ApoE -/-）小鼠和缺乏HDL相关胆固醇酯主要清除途径的清道夫受体BI基因敲除（SR-BI -/-）小鼠。尽管在这些小鼠中mTHPC在脂蛋白上的分布发生了变化，但mTHPC的药代动力学曲线保持不变。
我们得出结论，脂蛋白水平和胆固醇代谢均不影响血浆中mTHPC的药代动力学。
