Kaminskas Lisa M, Boyd Ben J, Karellas Peter, Henderson Scott A, Giannis Michael P, Krippner Guy Y, Porter Christopher J H
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Pde, Parkville, VIC 3052, Australia.
Mol Pharm. 2007 Nov-Dec;4(6):949-61. doi: 10.1021/mp070047s. Epub 2007 Oct 23.
Tritium-labeled poly- l-lysine dendrimers displaying 8 or 16 surface lysines have been capped with benzene sulfonate (BS), benzene disulfonate (BDS), or succinate (Succ) groups, and the intravenous pharmacokinetics and disposition profiles of the resulting dendrimers (Lys(8)(BS)(16), Lys(16)(BS)(32), Lys(16)(BDS)(32), Lys(16)(Succ)(32)) have been evaluated. Lys(16)(Succ)(32) was rapidly removed from the plasma primarily via renal elimination. Lys(16)(BS)(32) and Lys(16)(BDS)(32) were opsonized, resulting in more prolonged plasma elimination kinetics and increased uptake by the liver. Data obtained at higher doses suggested some evidence of nonlinear pharmacokinetics. Lys(8)(BS)(16) had reduced affinity for plasma proteins and was cleared more rapidly than the larger Lys(16)(BS)(32) or Lys(16)(BDS)(32) dendrimers. Lys(8)(BS)(16) and Lys(16)(BS)(32) were metabolized in vivo, resulting in the production of a low molecular weight species (possibly the cleavage product Lys(BS) (2)) that was extensively renally eliminated and accounted for almost all of the radioactivity recovered in urine ( approximately 20-45% of administered (3)H). In contrast, only 3-5% of the administered (3)H was recovered in the urine of rats administered Lys(16)(BDS)(32), suggesting increased resistance to in vivo degradation. The plasma clearance, distribution, and metabolic profiles of lysine dendrimers are therefore significantly influenced by the structure and charge of the capping groups. In particular, larger arylsulfonate-capped lysine dendrimers are rapidly opsonized and initially cleared from the plasma by the reticuloendothelial organs. The degree of metabolism is subsequently dictated by the nature of the surface capping group with BDS surfaces seemingly more resistant to breakdown. In contrast, smaller arylsulfonate-capped dendrimers are less readily opsonized and phagocytozed but are metabolically labile, and succinate-capped dendrimers are rapidly eliminated by the kidneys.
带有8个或16个表面赖氨酸的氚标记聚-L-赖氨酸树枝状聚合物已用苯磺酸盐（BS）、苯二磺酸盐（BDS）或琥珀酸盐（Succ）基团进行封端，并对所得树枝状聚合物（Lys(8)(BS)(16)、Lys(16)(BS)(32)、Lys(16)(BDS)(32)、Lys(16)(Succ)(32)）的静脉药代动力学和处置情况进行了评估。Lys(16)(Succ)(32)主要通过肾脏清除迅速从血浆中去除。Lys(16)(BS)(32)和Lys(16)(BDS)(32)被调理素化，导致血浆清除动力学延长，肝脏摄取增加。在较高剂量下获得的数据表明存在一些非线性药代动力学的证据。Lys(8)(BS)(16)对血浆蛋白的亲和力降低，比更大的Lys(16)(BS)(32)或Lys(16)(BDS)(32)树枝状聚合物清除得更快。Lys(8)(BS)(16)和Lys(16)(BS)(32)在体内代谢，产生一种低分子量物质（可能是裂解产物Lys(BS)(2)），该物质被广泛经肾脏清除，几乎占尿液中回收放射性的全部（约占给药(3)H的20 - 45%）。相比之下，给予Lys(16)(BDS)(32)的大鼠尿液中仅回收了3 - 5%的给药(3)H，表明其对体内降解的抵抗力增强。因此，赖氨酸树枝状聚合物的血浆清除、分布和代谢情况受到封端基团的结构和电荷的显著影响。特别是，较大的芳基磺酸盐封端的赖氨酸树枝状聚合物迅速被调理素化，并最初由网状内皮器官从血浆中清除。随后的代谢程度由表面封端基团的性质决定，BDS表面似乎对分解更具抵抗力。相比之下，较小的芳基磺酸盐封端的树枝状聚合物较不易被调理素化和吞噬，但代谢不稳定，而琥珀酸盐封端的树枝状聚合物则迅速被肾脏清除。
