Protease inhibitors are substrates of P gp and reverse transcriptase inhibitors are substrates of other transportation systems, largely OATs and MRPs. However, virtually all the drugs currently used for treating HIV infections enter the CNS poorly. The significance dub assay of adequate antiretroviral drug levels in the CNS led to evaluation of G gp inhibitors as a therapeutic modality to improve CNS distribution of antiretroviral protease inhibitors. In animal reports, the maximum influence of P gp inhibition was about the mind distribution of nelfinavir, and the most effective chemical was zosuquidar. The effect of zosuquidar was dose-dependent and increases in brain uptake of nelfinavir were around 18 fold in mice and 29 fold in rats. When ritonavir was along with saquinavir, ritonavir partly inhibited G gpmediated efflux of saquinavir from the mouse brain. In analogy to drug resistance in cancer, over-expression of P gp and other efflux transporters in epileptic foci may play a role in pharmacoresistant epilepsy. Nevertheless, while it is recognized that efflux transporters are upregulated in drug-resistant epileptogenic brain tissue in humans Immune system and mice, their role in elimination of anti-epileptic drugs in the brain is controversial. Hence, P gp inhibition by verapamil, administered directly into rat cerebral cortex, modestly increased the ISF to plasma concentration ratios of phenobarbital, phenytoin, lamotrigine, felbamate, carbamazepine or oxcarbazepine. Nonetheless, in rats with induced seizures, cyclosporine and tariquidar reversed opposition to several antiepileptic drugs and increased their brain to plasma concentration ratio without changing their plasma pharmacokinetics. Similar to antiepileptic drugs, G gp inhibition in rodents had only small impact conjugating enzyme on CNS distribution of a variety of antidepressnts and antipsychotic agents, including nortriptyline, fluphenazine, amisulpride, risperidone, and rizulide. When the plasma concentrations of the psychotropic drugs were inside their therapeutic range a few of these studies considered possible interactions. On the basis of the therapeutic indices of these compounds, Linnet and Ejsing proposed that even complete inhibition of P gp is unlikely to provide serious toxicity of these compounds and that in most cases possible clinical effects are likely to be limited. Another results of G gp inhibition in the BBB is increased CNS distribution and negative effects of G gp substrate drugs that usually do not cross the BBB and do not have central effects. Examples are the opioid loperamide, the dopaminergic antagonist domperidone and non-sedating anti-histamines. In a in situ perfusion research, quinidine resembled the effect of genetic KO of P gp in mice and increased the mind uptake of loperamide 9 collapse, suggesting near total G gp inhibition.