Simulated pharmacokinetics and pharmacodynamics during oral varenicline administration. (A) In the pharmacokinetic model for orally administered varenicline, the lungs are replaced by the digestive tract. The parameters derive from studies on humans (Faessel et al., 2006). The parameters are given in Table S2 and in Supplemental ZIP File. (B1) Varenicline concentrations in two compartments: the plasma/CSF/ER and the sequestered compartment. (B2) Effects on the two processes shown in A. Note that recommended treatment with varenicline almost completely activates nAChR protein chaperoning (inside-out process), but only slightly produces nAChR channel activation (outside-in process).