Zhang X, Zhang R, Zhao H, Cai H, Gush K A, Kerr R G, Pettit G R, Kraft A S
Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.
Cancer Res. 1996 Feb 15;56(4):802-8.
Bryostatin 1, a natural product anticancer agent isolated from a marine bryozoan, has been shown in tissue culture to activate protein kinase C. This agent has recently undergone Phase I testing in humans given either as a bolus i.v. injection or a continuous infusion. To understand how bryostatin 1 might be used best as an anticancer agent, a study of the pharmacokinetics, tissue distribution, metabolism, and elimination of bryostatin 1 in mice was undertaken, using [C26-3H]-labeled bryostatin 1. Following i.v. administration, the plasma disappearance curve for bryostatin 1 could be described by a two-compartment model, with half-lives of 1.05 and 22.97 h, respectively. In contrast, the plasma disappearance curve for bryostatin 1 administered i.p. was better described by a first order absorption one-compartment model, with an absorption half-life of 0.81 h and an elimination half-life of 28.76 h, respectively. The majority of radioactivity in plasma was associated with the intact drug for up to 24 h after dosing. In the first 12 h after i.v administration, urinary excretion represented the major pathway of elimination, with 23.0 +/- 1.9% (mean +/- SD) of the administered dose excreted. Within 72 h after i.v. administration, approximately equal amounts of radioactivity (40%) were excreted in feces compared to urine. Bryostatin 1 was widely distributed in many organs but concentrated in the lung, liver, gastrointestinal tract, and fatty tissue. The concentration in the gastrointestinal tract, along with the fecal excretion, suggests the possibility of enterohepatic circulation of this drug. In summary, this study demonstrates that bryostatin 1 is relatively stable in vivo, widely distributed but concentrated in some major tissues, and rapidly excreted first through urine and at later times through the feces. The data from this animal study should be useful in the design of future human trials with this anticancer drug.
苔藓抑素1是一种从海洋苔藓虫中分离出的天然产物抗癌剂，在组织培养中已显示可激活蛋白激酶C。该药物最近已在人体中进行了I期试验，给药方式为静脉推注或持续输注。为了了解苔藓抑素1作为抗癌剂的最佳使用方式，我们使用[C26 - 3H]标记的苔藓抑素1对小鼠体内苔藓抑素1的药代动力学、组织分布、代谢和消除进行了研究。静脉给药后，苔藓抑素1的血浆消除曲线可用二室模型描述，半衰期分别为1.05小时和22.97小时。相比之下，腹腔注射苔藓抑素1的血浆消除曲线用一级吸收单室模型描述更好，吸收半衰期为0.81小时，消除半衰期为28.76小时。给药后长达24小时，血浆中的大部分放射性与完整药物相关。静脉给药后的前12小时内，尿排泄是主要的消除途径，给药剂量的23.0±1.9%（平均值±标准差）经尿排出。静脉给药后72小时内，粪便中排出的放射性与尿液中排出的大致相等（40%）。苔藓抑素1广泛分布于许多器官，但在肺、肝、胃肠道和脂肪组织中浓度较高。胃肠道中的浓度以及粪便排泄表明该药物可能存在肠肝循环。总之，本研究表明苔藓抑素1在体内相对稳定，分布广泛但在一些主要组织中浓度较高，首先通过尿液快速排泄，随后通过粪便排泄。该动物研究的数据应有助于设计未来使用这种抗癌药物的人体试验。
