Assessment of the Kochak-Benet Equation for Hepatic Clearance for the Parallel-Tube Model: A Response to Jusko and Li.

This commentary seeks to clarify the relationships between conservation of mass, spatial continuity, advective mass transport, and first-order drug metabolism in the liver. It also provides additional insight into the meaning of clearance thereby proving that the Pang-Rowland equation and its extensions are incorrect. The Kochak-Benet equation has been verified and is not a rearrangement of the Pang-Rowland equation.

Critical Analysis of Hepatic Clearance Based on an Advection Mass Transfer Model and Mass Balance.

The relationship between liver blood flow rate and hepatic clearance has been derived and validated based on the constitutive principle of mass conservation using an advective mass transfer model for bivariate concentration, Ci (x, t). Metabolic elimination continuously diminishes along the blood flow path line, corresponding with the concentration gradient. Because of the constraint introduced by constant blood velocity, x and t are not independent variables. This requires the introduction of a new factor called the dwell time, which accounts for the time a drug is retained in the liver. First-order or saturable drug metabolism is dependent on perfusate drug concentration and the dwell time. A new extraction factor is explicitly identified as E = ln Cin/Cout. Because the isolated organ perfusion model described here is validated, it provides a basis for drawing inferences and exploring underlying features, mechanisms, and principles on which this model is based. In the conventional model, these underlying constitutive principles are unavailable. The concentration-time profile of a physiological-based elimination network is found to be inconsistent with the profile described by a pharmacokinetic model. For this reason, among others discussed, physiological-based models are incompatible with pharmacokinetic models and therefore cannot be used to explain systemic pharmacokinetic behavior.

Interfacially assembled carbohydrate nanocapsules: a hydrophilic macromolecule delivery platform.

A prospective approach was used to synthesize carbohydrate nanocapsules with a macromolecule payload and suitable interfacial properties for in vivo systemic circulation. Spatially directed carbohydrate assembly and polymerization resulted in structured hydrophilic vesicles with diameters of 200-300 nm. Mononucleated dispersions with monodisperse distributions were demonstrated in aqueous vehicles. The effects of pH, buffer capacity and reaction time on the molar degree of substitution of terephthaloyl chloride, trimesoyl chloride, and diethylmalonyl chloride were evaluated. The delivery of a test protein, lysozyme showed continuous release for 7 days. Immobilization of lysozyme caused by co-polymerization was 20% based on asymptotic recovery of released lysozyme. A theoretical shell thickness of 9.5 nm was estimated from a relative core volume of 80% and the average vesicle size.

Transepithelial ultrafiltration and fractal power diffusion of D-glucose in the perfused rat intestine.

Despite an enormous body of research investigating the mass transfer of D-glucose through biological membranes, carrier-mediated and first-order models have remained the prevalent models describing glucose's quantitative behavior even though they have proven to be inadequate over extended concentration ranges. Recent evidence from GLUT2 knockout studies further questions our understanding of molecular models, especially those employing Michaelis-Menten (MM)-type kinetic models. In this report, evidence is provided that D-glucose is absorbed by rat intestinal epithelium by a combination of convective ultrafiltration and nonlinear diffusion. The diffusive component of mass transfer is described by a concentration-dependent permeability coefficient, modeled as a fractal power function. Glucose and sodium chloride-dependent-induced aqueous convection currents are the result of prevailing oncotic and osmotic pressure effects, and a direct effect of glucose and sodium chloride on intestinal epithelium resulting in enhanced glucose, sodium ion, and water mobility. The fractal power model of glucose diffusion was superior to the conventional MM description. A convection-diffusion model of mass transfer adequately characterized glucose mass transfer over a 105-fold glucose concentration range in the presence and absence of sodium ion.