Nicotine and cotinine increases the brain penetration of saquinavir in rat

摘要: J. Neurochem. (2010) 115, 1495–1507. Abstract Endothelial tight junctions and efflux transporters of the blood–brain barrier (BBB) significantly limit brain accumulation many drugs, including protease inhibitors such as saquinavir. The cholinergic agonist nicotine is one most commonly used drugs in world incidence even higher human immune deficiency virus population (∼70%). We examined ability its primary metabolite cotinine to modify uptake saquinavir rats. Both at pharmacological concentrations matching those smokers, increased by two fold. Co-perfusion with nicotinic receptor antagonists passive permeability markers showed that effect was not caused activation or BBB disruption. Transport inhibition studies demonstrated limited multiple transporters, P-glycoprotein (P-gp), breast cancer resistance protein multidrug resistance-associated protein. In situ perfusion vitro experiments using a classical P-gp substrate rhodamine 123 linked transport. confirmed vivo chronic 14 day administration animals. These data suggest increases antiretroviral drug exposure may represent significant drug–drug interaction BBB. Although this slightly benefit CNS efficacy, it also expose potential serious neurotoxicity.