Pharmacokinetic modeling of absorption behavior of 9-aminocamptothecin (9-AC) released from colon-specific HPMA copolymer-9-AC conjugate in rats.
OBJECTIVE
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.
Gao
Song-Qi
SQ
Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA.
Sun
Yongen
Y
Kopecková
Pavla
P
Peterson
C Matthew
CM
Kopecek
Jindrich
J
D000465:Algorithms; D000779:Anesthetics, Local / Q000493:pharmacokinetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D002432:Cecum / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D016503:Drug Delivery Systems; D005772:Gastrointestinal Transit; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008012:Lidocaine / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D015233:Models, Statistical; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D000779:Anesthetics, Local; D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D008689:Methacrylates; C080125:9-aminocamptothecin; D008012:Lidocaine; C032802:hydroxypropyl methacrylate; D002166:Camptothecin