Pharmacokinetic characteristics and antitumor activity of the N-succinyl-chitosan-mitomycin C conjugate and the carboxymethyl-chitin-mitomycin C conjugate.
The conjugate between N-succinyl-chitosan (Suc-chitosan) and mitomycin C (MMC), named Suc-chitosan-MMC, and that between carboxymethyl-chitin (CM-chitin) and MMC, named CM-chitin-MMC, were investigated in vivo. As for the intraperitoneal drug administration using rats, the order of the maximum blood concentration of MMC was unconjugated MMC > CM-chitin-MMC > Suc-chitosan-MMC. The plasma concentration of MMC for Suc-chitosan-MMC was maintained at an almost constant level over 24 h. Pharmacokinetic analysis of each plasma concentration indicated that for each conjugate, the in vitro drug release reported previously was useful for the approximate estimation of the in vivo regeneration of MMC. The chemotherapeutic effect of MMC and the conjugates was investigated using mice bearing L1210 leukemia or B16 melanoma. Concerning antitumor activity against L1210 leukemia, the conjugates exhibited a marked effect at higher doses, and their effect increased even in the dose range where the effect of MMC decreased. MMC and the conjugates exhibited a good growth-inhibitory effect against B16 melanoma. Complete inhibition of growth of B16 melanoma was observed at the dose of 10 mg eq MMC/kg for CM-chitin-MMC.
Song
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Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
Onishi
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Nagai
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D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002686:Chitin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D048271:Chitosan; D002851:Chromatography, High Pressure Liquid; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007274:Injections, Intraperitoneal; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016685:Mitomycin / Q000097:blood / Q000493:pharmacokinetics; D008937:Mitomycins; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008937:Mitomycins; D002686:Chitin; D016685:Mitomycin; C044872:O-(carboxymethyl)chitin; D048271:Chitosan