MembranePlus (Simulations Plus, Inc.) was used to analyze the concentration-time profiles in donor and receiver compartments after apical and basolateral administration of 50 μg/mL (81.5 μM) indinavir alone and co-administration of 50 μg/mL (81.5 μM) indinavir with 70 μM vinblastine . The physicochemical properties of indinavir and vinblastine were predicted by ADMET PredictorTM 6.0 (Simulations Plus, Inc.). The contribution of paracellular diffusion was estimated from drug properties and the experimental setup. Carrier-mediated transport was modeled with Michaelis-Menten kinetics. The indinavir P-gp Vmax/Km ratio, along with parameters accounting for passive transcellular diffusion and membrane accumulation were fitted to the indinavir-alone data. This basic model was then applied to simulate the inhibition of P-gp by vinblastine by fitting the Vmax/Km ratio for indinavir with competitive inhibition of P-gp by vinblastine. The model also includes various effects of major experiment-related parameters (e.g, shaking rate, solvent pH, filter support and sampling effects). To develop a mechanistic mathematical model for analysis of in vitro permeability assays that accounts for all mechanisms contributing to observed apparent permeability: passive paracellular and transcellular diffusion, carrier-mediated transport, as well as drug accumulation in membranes and some intracellular compartments (e.g., lysosomes). The model was validated by analyzing the effect of competitive inhibition of P-gp by vinblastine on the apparent permeability of indinavir in Caco-2 monolayers.
By Ke X. Szeto, Viera Lukacova, Walter S. Woltosz, Michael B. Bolger