Nicotine from inhaled combustible cigarette smoke is delivered rapidly to the brain, and sufficient unbound nicotine concentrations exert pharmacological effects. In addition to nicotine, combustible cigarette smoke also contains a significant number of toxicants that trigger perturbations, leading to an altered steady state due to differential expression of proteins. In this study, a physiologically based pharmacokinetic (PBPK) model for inhaled nicotine was used to simulate the influence of lysosomal change-driven tissue retention and plasma protein binding levels on nicotine pharmacokinetics (PK). A 3 × increase in tissue lysosomal volumes lowered the nicotine brain maximum concentration (Cmax) by 20.8%. Similarly, a 50% increase in plasma protein binding also lowered the unbound plasma arterial nicotine Cmax by 39.4%. Such fundamental changes in nicotine disposition due to physiological changes in combustible cigarette smokers will lead to altered nicotine consumption and exposure-responses of other weakly basic drugs. Literature reports indicate that nicotine consumed from non-combustible products do not alter drug exposures, indicating fewer or less severe toxicant-driven perturbations with the use of these products. Although several other parameters influence nicotine PK, this PBPK modeling study shows that increased tissue retention and plasma protein binding reduce nicotine delivery to the brain and could lead to differential consumption of combustible cigarettes. These differences in physiological states among combustible cigarette smokers need to be evaluated and should be considered during therapeutic interventions.