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. 2008 Jan;25(1):218-26.
doi: 10.1007/s11095-007-9465-3. Epub 2007 Oct 11.

Pharmacokinetic modeling of absorption behavior of 9-aminocamptothecin (9-AC) released from colon-specific HPMA copolymer-9-AC conjugate in rats

Song-Qi Gao  1 , Yongen Sun, Pavla Kopecková, C Matthew Peterson, Jindrich Kopecek
Affiliations

Pharmacokinetic modeling of absorption behavior of 9-aminocamptothecin (9-AC) released from colon-specific HPMA copolymer-9-AC conjugate in rats

Song-Qi Gao et al. Pharm Res. 2008 Jan.

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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Figures

Fig. 1
Fig. 1
The structure of the HPMA copolymer–9-AC conjugate.
Fig. 2
Fig. 2
Degradation of HPMA copolymer–9-AC conjugate in rat cecal contents.
Fig. 3
Fig. 3
Absorption curve for the calculation of the absorption rate constant, ka. Remaining 9-AC concentration in the cecum during in situ absorption study.
Fig. 4
Fig. 4
Lidocaine extraction ratio through rat liver at a constant-input lidocaine concentration of 3.53 mg/l and flow rate of 10 ml/min.
Fig. 5
Fig. 5
Observed (dots) and predicted (curve) 9-AC plasma concentration-time profiles after intravenous administration of 9-AC to rats.
Fig. 6
Fig. 6
Pharmacokinetic model describing GI transit and absorption after oral administration of HPMA copolymer–9-AC conjugate.
Fig. 7
Fig. 7
Model-predicted plasma concentration-time profile and observed data (dots) after oral administration of HPMA copolymer–9-AC conjugate to rats. Broken line represents predicted curve without metabolism, solid line represents predicted curve after metabolism.
Fig. 8
Fig. 8
GI-transit dose-time profile for the HPMA copolymer–9AC conjugate and released 9-AC after oral administration of the conjugate to rats; solid line represents released 9-AC from the polymer conjugate in cecum; dashed line represents HPMA copolymer–9-AC-conjugate in stomach and SI; broken line represents HPMA copolymer–9-AC-conjugate in cecum.
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