<p>P-glycoprotein (P-gp) is a key efflux transporter and may be involved in drug-drug interactions (DDIs) at the blood-brain barrier (BBB), which could lead to changes in central nervous system (CNS) drug exposure. Morphine is a P-gp substrate and therefore a potential victim drug for P-gp mediated DDIs. It is however unclear if P-gp inhibitors can induce clinically relevant changes in morphine CNS exposure. Here, we used a physiologically-based pharmacokinetic (PBPK) model-based approach to evaluate the potential impact of DDIs on BBB transport of morphine by clinically relevant P-gp inhibitor drugs.</p><p>The LeiCNS-PK3.0 PBPK model was used to simulate morphine distribution at the brain extracellular fluid (brain_ECF) for different clinical intravenous dosing regimens of morphine, alone or in combination with a P-gp inhibitor. We included 34 commonly used P-gp inhibitor drugs, with inhibitory constants and expected clinical P-gp inhibitor concentrations derived from literature. The DDI impact was evaluated by the change in brain_ECF exposure for morphine alone or in combination with different inhibitors. Our analysis demonstrated that P-gp inhibitors had a negligible effect on morphine brain_ECF exposure in the majority of simulated population, caused by low P-gp inhibition. Sensitivity analyses showed neither major effects of increasing the inhibitory concentration nor changing the inhibitory constant on morphine brain_ECF exposure. In conclusion, P-gp mediated DDIs on morphine BBB transport for the evaluated P-gp inhibitors are unlikely to induce meaningful changes in clinically relevant morphine CNS exposure. The developed CNS PBPK modeling approach provides a general approach for evaluating BBB transporter DDIs in humans.</p>