Availability predictions by hepatic elimination models for Michaelis-Menten kinetics

Abstract

Numerical methods have been used to compare the availability predictions of a number of hepatic elimination models when Michaelis-Menten kinetics is operative. Propranolol and galactose were used as model compounds. Lower availabilities were predicted by the dispersion model than by a segregated distribution model for both compounds. The differences in the predictions were most pronounced for models corresponding to a large variation in solute residence times in the liver. The predictions of the tank-in-series, dispersion model with mixed boundary conditions and dispersion model with Dankwerts boundary conditions were similar over all concentrations studied. Changes in blood flow and protein binding provided little discrimination between the model predictions. It is concluded that micromixing of blood between sinusoids and the anatomical sites of mixing are important determinants of availability when liver eliminating enzymes are partially saturated.

Analysis Methods and Recent Advances in Nonlinear Pharmacokinetics from In Vitro through In Loci to In Vivo

“…Because CLH calculated from Eq. (24) was almost independent of dose, this shows that the dose-dependence of CL is due mainly to that of CLR.…”

“…Equation (8) 19,20) tank-inseries 21) and dispersion models, [22][23][24] there is no simple relationship between Cin and Cout such as those shown in Eqs. (6) and (8).…”

Notes on the inverse gaussian distribution and choice of boundary conditions for the dispersion model in the analysis of local pharmacokinetics

“…4,5,9,10,14,25 From an empirical viewpoint, it is relevant if the model explains real data properly. However, for greatly spreading curves, the appropriateness of the shape needs to be verified because the influence of the improper boundary definitions of its generating function becomes apparent.…”

“…DBC is defined as follows: 2,5,13 where C in is the concentration in the entering stream. MBC is expressed as follows: 2,5,14 The analytical solution of the dispersion model after bolus input with MBC is given by: 2 where the elimination is not considered. As described above, eq 6 also represents the inverse Gaussian distribution.…”

“…7,20,21 In addition, several numerical methods have been introduced to calculate the dispersion model for nonlinear kinetics. 14,[22][23][24] It is now possible to obtain non-steady-state solutions of nonlinear multicompartment dispersion models with any input function. 23…”