Tissue-to-plasma partition coefficients of the drugs.

<p>Tissue-to-plasma partition coefficients of the drugs.</p

Summary of 10 <i>in vivo</i> clinical studies used in comparison to the simulations.

<p>Summary of 10 <i>in vivo</i> clinical studies used in comparison to the simulations.</p

Simulated enzyme levels as a function of time.

<p>The total enzyne level (free enzyne + enzyme-substrate complex) is represented as a fold change compared to the initial level. The color gradient indicates the positions within the lobule from blue (Entrance of the lobule) to red (Exit of the lobule): (A) Azithromycin (MBI inducer) (B) Cimetidine (Reversible inhibitor: No effect on enzyme level) (C) Ethinyl Estradiol (MBI inhibitor and inducer: It seems that in this case the effect cancels each other out) (D) Rifampin (Inducer).</p

Simulated PK profile for midazolam after an oral dose of 15 mg and comparison to clinical data.

<p>(⋆) Fee <i>et al</i>. 1987 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183794#pone.0183794.ref020" target="_blank">20</a>] (•) Zimmermann <i>et al</i>. 1996 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183794#pone.0183794.ref019" target="_blank">19</a>].</p

Lobule geometry and modelling.

<p>(A) The lobule cross section as represented displays an apparent elementary symmetry essential for its physiology primarily given by the blood vessels and the blood flow (Credit to Dr. Roger C. Wagner, University of Delaware). (B) This symmetry is used when lobule modeling or representation are involved. In general, a lobule is represented by a hexagon composed of hepatocyte plates. These plates are hierarchically organized to optimize exchanges. (C) To model the blood flow (and subsequent exchanges between the liver tissues and the blood), an algorithm was designed to automatically generate the length and radius of the sinusoids. The latter is used to estimate the changes in velocity within a sinusoid portion by assuming a constant blood flow and a constant velocity over the cross section.</p

DDI prediction for the 10 clinical studies.

<p>DDI prediction for the 10 clinical studies.</p

Properties of 5 sinusoid levels from the lobule model.

<p>(A) The radius of the sinusoids is expressed as a function of the distance to the periphery of the lobule. For a given level, the radius is decreasing as the sinusoids are converging toward the center of the lobule. Once the sinusoids reach their minimum size they merge together which increases the radius size in a stepwise manner. (B) The flow of the sinusoids is expressed as a function of the distance to the periphery of the lobule. For a given level, the flow is constant, but double when two sinusoids merge. (C) The velocity of the sinusoids is expressed as a function of the distance to the periphery of the lobule. For a given level, the velocity is increasing as the sinusoid radius is decreasing. Once the sinusoids reach their minimum size they merge which decreases the blood velocity suddenly.</p

Simulated PK profiles for midazolam with a placebo (blue) or a perpetrator (orange) and comparison to clinical data.

<p>The dots represent the clinical observations: (A) Azithromycin [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183794#pone.0183794.ref019" target="_blank">19</a>] (B) Cimetidine [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183794#pone.0183794.ref020" target="_blank">20</a>] (C) Ethinyl Estradiol [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183794#pone.0183794.ref023" target="_blank">23</a>] (D) Rifampin [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183794#pone.0183794.ref028" target="_blank">28</a>].</p

Simulated PK of the perpetrator (blue) and victim (orange) drugs.

<p>The simulation were run using the clinical dose regimens from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183794#pone.0183794.t002" target="_blank">Table 2</a>: (A) Azithromycin (B) Cimetidine (C) Ethinyl Estradiol (D) Rifampin.</p

The seven compartmental model.

<p>Red and blue arrows represent blood flows (<i>Q</i>_<i>i</i> where <i>i</i> represents: <i>T</i> for total blood flow, <i>ha</i> hepatic artery blood flow, <i>pv</i> portal vein blood flow, <i>L</i> for the liver blood flow, <i>G</i> for the gut blood flow, <i>K</i> for the kidneys blood flow and <i>RB</i> for the blood flow going to the rest of the body). The black arrows represent absorption (<i>k</i>_<i>a</i>: absorption constant rate) or excretion (<i>CL</i>_<i>R</i>: Renal Clearance).</p