A delayed nonlinear PBPK model for genistein dosimetry in rats.
Genistein is an endocrine-active compound (EAC) found in soy products. It has been linked to beneficial effects such as mammary tumor growth suppression and adverse endocrine-related effects such as reduced birth weight in rats and humans. In its conjugated form, genistein is excreted in the bile, which is a significant factor in its pharmacokinetics. Experimental data suggest that genistein induces a concentration-dependent suppression of biliary excretion. In this article, we describe a physiologically based pharmacokinetic (PBPK) model that focuses on biliary excretion with the goal of accurately simulating the observed suppression. The mathematical model is a system of nonlinear differential equations with state-dependent delay to describe biliary excretion. The model was analyzed to examine local existence and uniqueness of a solution to the equations. Furthermore, unknown parameters were estimated, and the mathematical model was compared against published experimental data.
Zager
Michael G
MG
North Carolina State University, Center for Research in Scientific Computation, Box 8205, Harrelson Hall, Raleigh, NC 27695-8205, USA. Michael.Zager@pfizer.com
Schlosser
Paul M
PM
Tran
Hien T
HT
D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D019833:Genistein / Q000493:pharmacokinetics* / Q000494:pharmacology; D008954:Models, Biological; D017711:Nonlinear Dynamics; D051381:Rats
D019833:Genistein