Abstract

Minimal physiologically based pharmacokinetic (mPBPK) models are physiologically relevant, require less information than full PBPK models, and offer flexibility in pharmacokinetics (PK). The well-stirred hepatic model (WSM) is commonly used in PBPK, whereas the more plausible dispersion model (DM) poses computational complexities. The series-compartment model (SCM) mimics the DM but is easier to operate. This work implements the SCM and mPBPK models for assessing fractional tissue distribution, oral absorption, and hepatic clearance using literature-reported blood and liver concentration-time data in rats for compounds mainly cleared by the liver. Further handled were various complexities, including nonlinear hepatic binding and metabolism, differing absorption kinetics, and sites of administration. The SCM containing one to five (n) liver subcompartments yields similar fittings and provides comparable estimates for hepatic extraction ratio (ER), prehepatic availability (F_g), and first-order absorption rate constants (k_a). However, they produce decreased intrinsic clearances (CL_int) and liver-to-plasma partition coefficients (K_ph) with increasing n as expected. Model simulations demonstrated changes in intravenous and oral PK profiles with alterations in K_ph and k_a and with hepatic metabolic zonation. The permeability (PAMPA P) of the various compounds well explained the fitted fractional distribution (f_d) parameters. The SCM and mPBPK models offer advantages in distinguishing systemic, extrahepatic, and hepatic clearances. The SCM allows for incorporation of liver zonation and is useful in assessing changes in internal concentration gradients potentially masked by similar blood PK profiles. Improved assessment of intraorgan drug concentrations may offer insights into active moieties driving metabolism, biliary excretion, pharmacodynamics, and hepatic toxicity.