(A) Schematic illustration of a tumor vessel illustrating loss of smooth muscle cells, local degradation of the extracellular matrix, and increased permeability of the endothelium. (B) Illustration of the pharmacokinetic model taking into account the EPR effect. The rate constants kp and kd describe exchange with the peripheral volume. The rate constants kepr and kb describe extravasation from circulation into the tumor, and intravasation back into the circulation, respectively. The rate constant kel represents clearance by the kidneys, MPS, and any other non-tumor elimination processes, such that when kb = 0, k10 = kepr + kel where kel is the elimination rate constant. (C) Standard two compartment model with central and peripheral compartments. c1 and c2 represent the drug concentration in blood (central compartment) and normal tissue (peripheral compartment), respectively. The first order rate constant k10 describes all elimination pathways, including clearance by the kidneys, uptake by the MPS, and tumor accumulation. The first order rate constants k12 and k21 describe exchange between the two compartments. Note that kp = k12, kd = k21. (D) Two compartment model defined in terms of the drug amount, where Nbl is the amount of drug in blood (mg), and Np is the amount in peripheral tissue (mg). (E) Three compartment model with the addition of a tumor “compartment” where Nt is the amount of drug in the tumor. Exchange with the tumor is described by the rate constants kepr and kb, respectively. The rate constant kel describes elimination pathways including clearance by the kidneys and uptake by the MPS, but does not include tumor accumulation.<sup id="cite_ref-1" class="reference"><a href="#cite_note-1">[1]</a></sup>
Andrew D. Wong, Mao Ye, Martin B. Ulmschneider, Peter C. Searson
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