Fig. 1.

Passive and active processes of drug movement across the basolateral and apical membranes of kidney proximal tubule cells. ^a For all drug models in this study, a full physiologically based pharmacokinetic (PBPK) model in Simcyp Simulator^® was used. The kidney compartment used a ‘mechanistic kidney module’ with major transporters [1], which has been simplified in the figure with urine, tubule cell and blood compartments to illustrate the three major renal clearance processes: passive diffusion clearance (CL_pd, on both membranes), net uptake of the drug into tubule cells from the blood (intrinsic transporter clearance, CL_int,T), and net efflux of drug into the urine from the cells (efflux intrinsic transporter clearance, CL_int,efflux). ^b Net basolateral uptake and apical efflux are represented by ‘lumped’ transporter processes T_up,b and T_eff,a; each is composed of different transporters that move drugs in different directions at each side of the tubular cell. ADME absorption, distribution, metabolism, and excretion, B/P blood to plasma partition ratio, CL_int,T,eff efflux transporter-mediated intrinsic clearance, CL_int,T,up uptake transporter-mediated intrinsic clearance, CL_iv in vivo clearance, CL_r renal clearance, CL_r,T renal clearance mediated by a transporter, f_a fraction available from dosage form, f_u,p fraction unbound in plasma, k_a first-order absorption rate constant, LogP partition coefficient, MW molecular weight, P_eff,man effective permeability, pKa dissociation constant, V_ss volume of distribution at steady state