Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma.
BACKGROUND
Enterohepatic recirculation of irinotecan and one of its metabolites, SN-38, has been observed in pharmacokinetic data sets from previous studies. A mathematical model that can incorporate this phenomenon was developed to describe the pharmacokinetics of irinotecan and its metabolites.


METHODS
A total of 32 patients with recurrent malignant glioma were treated with weekly intravenous administration of irinotecan at a dose of 125 mg/m(2). Plasma concentrations of irinotecan and its three major metabolites were determined. Pharmacokinetic models were developed and tested for simultaneous fit of parent drug and metabolites, including a recirculation component.


RESULTS
Rebound in the plasma concentration suggestive of enterohepatic recirculation at approximately 0.5-1 h post-infusion was observed in most irinotecan plasma concentration profiles, and in some plasma profiles of the SN-38 metabolite. A multi-compartment model containing a recirculation chain was developed to describe this process. The recirculation model was optimal in 22 of the 32 patients compared to the traditional model without the recirculation component.


CONCLUSIONS
A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears to improve characterization of this drug's disposition in patients with glioma.
Younis
Islam R
IR
Department of Basic Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA.
Malone
Samuel
S
Friedman
Henry S
HS
Schaaf
Larry J
LJ
Petros
William P
WP
D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004764:Enterohepatic Circulation; D005260:Female; D005910:Glioma / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D008297:Male
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin