期刊
PHARMACEUTICAL RESEARCH
卷 25, 期 1, 页码 218-226出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-007-9465-3
关键词
absorption prediction; colon-specific drug delivery; HPMA copolymer-9-aminocamptothecin conjugate; oral dosing; pharmacokinetic modeling
资金
- NCI NIH HHS [R01 CA051578-15, R01 CA051578, CA 51578, R01 CA051578-16] Funding Source: Medline
- NIGMS NIH HHS [R01 GM050839-05, GM 50839] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA051578] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM050839] Funding Source: NIH RePORTER
Purpose. To quantitate and predict colon-specific 9-aminocamptothecin (9-AC) release from the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-9-AC conjugate and its absorption behavior after oral administration in rats. Methods. Drug distribution in the gastrointestinal (GI) tract and the plasma concentration-time profile of 9-AC released from the HPMA copolymer conjugate were predicted using the degradation, transit, and absorption rate constants in cecum. The fate of 9-AC in cecum and liver was measured by in-situ cecum absorption and liver perfusion. Results. Following oral administration of the conjugate, 9-AC was released rapidly in cecum. Based on the pharmacokinetic model, up to 60% of the dose was in the cecum at similar to 6 h, and 7% of the dose still remained there at 24 h. The predicted plasma concentration curve for released 9-AC after an oral dose of 3 mg/kg of 9-AC equivalent increased gradually and reached a peak of 98 nM at 7 h, then started decreasing slowly to 16 nM at 24 h. The bioavailability value was estimated as 0.31 after the first-pass elimination. Conclusions. A pharmacokinetic model delineated the impact of GI transit, drug absorption rate, and first-pass metabolism on drug disposition following oral administration of HPMA copolymer-9-AC conjugate in rats.
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