Pharmacokinetics and pharmacology of hirulog-like peptide.

Hirulog-like peptide (HLP), a new thrombin peptide inhibitor, effectively reduces neointimal formation or restenosis in rat and rabbit vascular injury models. The present study investigated the pharmacokinetics and pharmacology of HLP in Sprague-Dawley (SD) rats. The input response of HLP in rats was studied using radioisotopic tracing method. Male SD rats were intravenously injected with a single dose of I-HLP (3.2, 6.4, or 12.8 mg/kg) for pharmacokinetic analysis. The concentration-time curve of I-HLP following bolus injection fitted a 3-compartment model. The half-life of HLP in rats was between 25 and 31 min following 3.2 to 12.8 mg/kg of bolus injection. Radioactivity of I-HLP was detected in all tested tissues and was most abundant in kidneys or stomachs. Blood pressure, respiratory frequency, and heart rates were not significantly altered during continuous intravenous infusion with saline or 1.6 to 3.2 mg/kg/h of HLP for 4 h. Bleeding time and activated partial thromboplastin time were significantly prolonged in rats infused with HLP compared to vehicle. ADP-induced platelet aggregation was significantly reduced in the HLP-treated groups compared with controls. The results suggest that HLP possesses first-order kinetic characteristics. HLP is secreted mainly through kidneys. Beside its anticoagulant activity, no other adverse effect was detected in SD rats receiving HLP.

Body distribution and in situ evading of phagocytic uptake by macrophages of long-circulating poly (ethylene glycol) cyanoacrylate-co-n-hexadecyl cyanoacrylate nanoparticles.

AIM: To investigate the body distribution in mice of [14C]-labeled poly methoxyethyleneglycol cyanoacrylate-co-n-hexadecyl cyanoacrylate (PEG-PHDCA) nanoparticles and in situ evading of phagocytic uptake by mouse peritoneal macrophages. METHODS: PEG-PHDCA copolymers were synthesized by condensation of methoxypolyethylene glycol cyanoacetate with [14C]-hexadecyl-cyanoacetate. [14C]-nanoparticles were prepared using the nanoprecipitation/solvent diffusion method, while fluorescent nanoparticles were prepared by incorporating rhodamine B. In situ phagocytic uptake was evaluated by flow cytometry. Body distribution in mice was evaluated by determining radioactivity in tissues using a scintillation method. RESULTS: Phagocytic uptake by macrophages can be efficiently evaded by fluorescent PEG-PHDCA nanoparticles. After 48 h, 31% of the radioactivity of the stealth [14C]-PEG-PHDCA nanoparticles after iv injection was still found in blood, whereas non-stealth PHDCA nanoparticles were cleaned up from the bloodstream in a short time. The distribution of stealth PEG-PHDCA nanoparticles and non-stealth PHDCA nanoparticals in mice was poor in lung, kidney, and brain, and a little higher in hearts. Lymphatic accumulation was unusually high for both stealth and non-stealth nanoparticles, typical of lymphatic capture. The accumulation of stealth PEG-PHDCA nanoparticles in the spleen was 1.7 times as much as that of non-stealth PHDCA (P< 0.01). But the accumulation of stealth PEG-PHDCA nanoparticles in the liver was 0.8 times as much as that of non-stealth PHDCA (P< 0.05). CONCLUSION: PEGylation leads to long-circulation of nanoparticles in the bloodstream, and splenotropic accumulation opens up the potential for further development of spleen-targeted drug delivery.