Exploring the Pharmacokinetic Mysteries of the Liver: Application of Series Compartment Models of Hepatic Elimination

Abstract

extraction ratio; F, hepatic availability; FTY720, fingolimod; f ub , unbound fraction in blood; IV, intravenous; IVIVE, in vitro-to-in vivo extrapolation; K p , tissue-to-plasma partition coefficient; n, number of liver sub-compartments; PBPK, physiologically-based pharmacokinetic; PD, pharmacodynamic; PK, pharmacokinetic; PTM, parallel tube model; R b , blood-to-plasma ratio; SS, steady state; T max , time to reach C max ; VEM, verapamil; WSM, well-stirred model.

Utility of Minimal Physiologically Based Pharmacokinetic Models for Assessing Fractional Distribution, Oral Absorption, and Series-Compartment Models of Hepatic Clearance

“…12-13 and 19-21 without the components in red). As was done in our most recent work (Li and Jusko, 2023), the SCM containing 1, 2, and 5 liver sub-compartments were selected herein to mathematically mimic the WSM, and the DM with D N = 0.6 and 0.1, the upper and lower boundaries of the commonly reported D N range for the liver (Diaz-Garcia et al, 1992;Chou et al, 1993;Oliver et al, 2001). The CL int and K ph were simultaneously estimated with the hepatic ER being obtained as a secondary parameter using Eq.…”

“…To further explore the impacts of changing K ph or k a , and metabolic enzyme zonation on IV and oral PK profiles in the blood, liver, and each of the liver sub-compartments, model simulations were performed for NIC, DLZ, and DPH using the mPBPK model extended with the SCM under the following conditions: 1) different K ph values (i.e., K ph , ±2-fold K ph , and ±5-fold K ph ); 2) different k a values (i.e., k a , ±2-fold k a , and ±5-fold k a ); 3) different patterns of hepatic enzyme zonation as were assumed previously (Li and Jusko, 2023), i.e., either lower metabolic activity at the periportal (PP) region assuming F i+1 = F i 2 (i=1, 2…4):…”

“…The minimal-PBPK model with one or two tissue compartments extended with the SCM of hepatic elimination is shown in Fig 1 . The SCM has been described in detail (Li and Jusko, 2023). Briefly, the liver is divided into n well-stirred sub-compartments connected by hepatic blood flow (Q h ), and the tissue volume (V hi ), availability (F i ), extraction ratio (ER i ), and intrinsic clearance (CL int,i ) for each sub-compartment i (i=1, 2, 3…n) are initially assumed to be identical:…”

“…3B). According to the quantitative correlations between the SCM and the basic hepatic clearance models demonstrated previously (Li and Jusko, 2023), the comparisons of CL int and K ph were made between the SCM with n=1…”

“…Subsequently, variants of the SCM were applied to mimic the DM for characterizing the hepatic disposition of transporter substrates (Watanabe et al, 2009;Jones et al, 2012;Li et al, 2014;Morse et al, 2017) and predicting the clinical drug-drug interactions (DDIs) involving hepatic transporters/enzymes (Asaumi et al, 2019;Zhang et al, 2022). The quantitative correlation of the SCM and DM was not elucidated until our recent work (Li and Jusko, 2023), where we demonstrated how the number of liver sub-compartments (n) in the SCM correlated with the dispersion number (D N ) of the DM that describes the relative spread of solute on passage through the liver. We also showed that the SCM closely resembles the DM 9 (CAR) T cells (Tsai et al, 2022) and the PK of antenatal betamethasone and dexamethasone in parturient women and their fetuses (Krzyzanski et al, 2023).…”