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Pharmacokinetic Modeling of Absorption Behavior of 9-Aminocamptothecin (9-AC) Released from Colon-specific HPMA Copolymer–9-AC Conjugate in Rats

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ABSTRACT

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 ~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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ACKNOWLEDGMENT

The research was supported in part by NIH grants GM50839 and CA51578. 9-Aminocamptothecin was kindly provided by National Cancer Institute, Division of Cancer Treatment and Diagnosis.

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Authors and Affiliations

  1. Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah, 84112, USA

    Song-Qi Gao, Pavla Kopečková & Jindřich Kopeček

  2. Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, 84112, USA

    Yongen Sun & C. Matthew Peterson

  3. Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112, USA

    Pavla Kopečková & Jindřich Kopeček

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  1. Song-Qi Gao
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Correspondence to Jindřich Kopeček.

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Gao, SQ., Sun, Y., Kopečková, P. et al. Pharmacokinetic Modeling of Absorption Behavior of 9-Aminocamptothecin (9-AC) Released from Colon-specific HPMA Copolymer–9-AC Conjugate in Rats. Pharm Res 25, 218–226 (2008). https://doi.org/10.1007/s11095-007-9465-3

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  • DOI: https://doi.org/10.1007/s11095-007-9465-3

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