Journal
JOURNAL OF DRUG TARGETING
Volume 22, Issue 3, Pages 200-210Publisher
INFORMA HEALTHCARE
DOI: 10.3109/1061186X.2013.856011
Keywords
2-Glucosamine; renal ischemia reperfusion; toxicity; triptolide
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Funding
- National Basic Research Programs of China (973 program) [2012CB724002]
- National Natural Science Foundation of China [81130060]
- National S &T Major Project of China [2011ZX09310-002]
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Purpose: This study examined whether a triptolide-glucosamine conjugate (TPG) would show better renal accumulation and few side effects than triptolide (TP) on its own, thereby improving the drug's protective effects against renal ischemia-reperfusion (I/R) injury. Methods: TP was coupled via carbamate bond to 2-glucosamine to generate TPG. The TPG and TP were compared in terms of their in vitro stability, cytotoxicity, in vivo biodistribution, protective effects against renal I/R injury and toxicity. Results: Successful synthesis of TPG was confirmed by H-1 nuclear magnetic resonance (NMR), 13 C NMR, UV spectroscopy and mass spectrometry. After intravenous injection in mice, TPG showed a renal concentration 44.7-fold higher than that of TP at 60 min ( p < 0.01), and the area under the curve (AUC) for TPG in kidneys was 3.29-fold higher than that for TP ( p < 0.01). TPG also ameliorated the progression of renal I/R injury more effectively than TP did. TPG was associated with less toxicity to the liver, male reproductive system and immune system than was TP. Conclusion: TPG shows greater efficacy and lower toxicity than TP alone in mice and rats, suggesting that it merits further study in clinical trials as a potential next-generation treatment for immunological renal diseases.
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