| Autor: |
M. Kaminskas, Lisa, J. Boyd, Ben, Karellas, Peter, A. Henderson, Scott, P. Giannis, Michael, Y. Krippner, Guy, J. H. Porter, Christopher |
| Zdroj: |
Molecular Pharmaceutics; October 2007, Vol. 4 Issue: 6 p949-961, 13p |
| Abstrakt: |
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) 32was rapidly removed from the plasma primarily via renal elimination. Lys 16(BS) 32and Lys 16(BDS) 32were 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) 16had reduced affinity for plasma proteins and was cleared more rapidly than the larger Lys 16(BS) 32or Lys 16(BDS) 32dendrimers. Lys 8(BS) 16and Lys 16(BS) 32were 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 (∼20–45% of administered 3H). In contrast, only 3–5% of the administered 3H 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. |
| Databáze: |
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