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Predicting plasma profiles following oral dosing for drug liver transporter substrates using physiologically based pharmacokinetic modeling
Author(s) -
Gosset James Richard,
Jones Hannah M,
Lai Yurong,
Barton Hugh A
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb624
Subject(s) - physiologically based pharmacokinetic modelling , pharmacokinetics , pharmacology , transporter , bioavailability , dosing , chemistry , absorption (acoustics) , drug , oral administration , chromatography , medicine , biochemistry , materials science , composite material , gene
The aim of this work was to assess the prediction of oral plasma profiles utilizing a previously developed physiologically based pharmacokinetic (PBPK) approach using in vitro sandwich cultured hepatocytes (SCHH) to predict intravenous plasma profiles for seven liver transporter substrates (Jones et al., 2012). Utilizing physicochemical, in vitro passive permeability and solubility inputs, descriptors of oral absorption were predicted using a physiologically based gastrointestinal tract model. These inputs were then incorporated into the published transporter PBPK model with a single compartment for oral absorption. The validity of these absorption predictions were shown to be satisfactory when assessed by combining them with the transporter parameters obtained from fitting the intravenous plasma data. Prospective predictions based on SCHH utilizing scaling factors developed in the literature and predicted oral absorption parameters were performed as a test of both aspects in predicting oral plasma time course. The average fold errors for the seven compounds increased somewhat to 2.5, 3.3, and 2.4, respectively. An early prediction method has been developed using physicochemical and in vitro inputs to estimate plasma profiles and pharmacokinetic parameters for intravenous and oral dosing drugs that are substrates for liver transporters.