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1. Mol Pharm. 2012 Jan 20. [Epub ahead of print]

In silico modeling for the non-linear absorption kinetics of UK-343,664: a P-gp
and CYP3A4 substrate.

Abuasal BS, Bolger MB, Walker DK, Kaddoumi A.

The aim of this work was to extrapolate in vitro and preclinical animal data to
simulate the pharmacokinetic parameters of UK-343,664, a P-glycoprotein (P-gp)
and CYP3A4 substrate, in human. In addition, to develop a simulation model to
demonstrate the involvement and the controversial complex interaction of
intestinal P-gp and CYP3A4 in its non-linear absorption, first-pass extraction,
and pharmacokinetics using the advanced compartmental absorption and transit
(ACAT) model. Finally, to compare the results predicted from the model to the
reported findings in human clinical studies. In situ perfusion, allometric
scaling, PBPK Rodger mechanistic approach, in vitro metabolism, and fitting to in
vivo data were used to mechanistically explain the absorption, distribution and
metabolism, respectively. GastroPlus™ was used to build the integrated simulation
model in human for UK-343,664 to mechanistically explain the observed clinical
data at 30, 100, 200, 400, and 800 mg oral doses. The measured in vitro value for
CYP3A4 Km (465 uM) in rCYPs was converted to units of ug/mL, corrected for
assumed microsomal binding (17.8%) and applied to all metabolic processes. The
measured in vitro values of Vmax for CYP3A4 (38.9 pmol/min/pmol), 2C8, 2C9, 2C19,
and 2D6 were used along with the in vitro CYP3A4 Km to simulate liver first pass
extraction and systemic clearance. The measured in vitro values of Vmax for
CYP3A4 and 2D6 were used along with the in vitro CYP3A4 Km to simulate gut first
pass extraction. Vmax and Km values for P-gp were obtained by fitting to in vivo
data and used to simulate gut efflux transport activity. Investigation of the
interaction mechanism of P-gp and CYP3A4 in the intestine was achieved by
comparing the influence of a virtual knockout of P-gp or gut metabolism on the
fraction absorbed, fraction reaching the portal vein, and fraction metabolized in
the gut. Comparison between simulation and in vivo results showed that the in
silico simulation provided a mechanistic explanation of the observed non-linear
absorption kinetics of UK-343,664 in human following its administration in the
range of 30-800 mg as oral solutions. The simulation results of the
pharmacokinetic parameters, AUC and Cmax, by GastroPlus were comparable with
those observed in vivo. This simulation model is one possible mechanistic
explanation of the observed in vivo data and suggests that the non-linear dose
dependence could be attributed to saturation of both the efflux transport by P-gp
and the intestinal metabolism. However, the concentration ranges for either
protein saturation did not overlap and resulted in much greater than dose
proportional increases in AUC. At low doses, producing intra-enterocyte
concentrations below the fitted value of Km for P-gp, the influence of P-gp
appears to be protective and results in a lower fraction of gut 3A4 metabolism.
At higher doses, as P-gp becomes saturated the fraction of gut 3A4 extraction
increases, and eventually at the highest doses, where 3A4 becomes saturated, the
fraction of gut 3A4 extraction again decreases. Such a complex interpretation of
this in vitro-in vivo extrapolation (IVIVE) is another example of the value and
insight obtained by physiologically-based absorption simulation.

PMID: 22264132 [PubMed - as supplied by publisher]