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Permeability, Transport, and Metabolism of Solutes in Caco-2 Cell Monolayers: A Theoretical Study

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada

We explored the properties of a catenary model that includes the basolateral (B), apical (A), and cellular compartments via simulations under linear and nonlinear conditions to understand the asymmetric observations arising from transporters, enzymes, and permeability in Caco-2 cells. The efflux ratio (EfR; P_app,BA/P_app,AB), obtained from the effective permeability from the AB and BA direction under linear conditions, was unity for passively permeable drugs whose transport does not involve transporters; the value was unaffected by cellular binding or metabolism, but increased with apical efflux. Metabolism was asymmetric, showing lesser metabolite accrual for the BA than AB direction because of inherent differences in the volumes for A and B. Moreover, the net flux (total - passive permeation) due to saturable apical efflux, absorption, or metabolism showed nonconformity to simple Michaelis-Menten kinetics against C_D,0, the loading donor concentration. EfR values differed with saturable apical efflux and metabolism (>1), as well as apical absorption (EfRs <1), but approached unity with high passive diffusive clearance (CL_d) and increasing C_D,0 at a higher degree of saturation of the process. The J_max (apparent V_max estimated for the carrier system) and [or the based on a modified equation with the Hill coefficient (β)] estimates from the Eadie-Hofstee plot revealed spurious correlations with the assigned V_max and K_m. The sampling time, CL_d, and parameter space of K_m and V_max strongly influenced both the correlation and accuracy of estimates. Improved correlation was found for compounds with high CL_d. These observations showed that the catenary model is appropriate in the description of transport and metabolic data in Caco-2 cells.

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