RT Journal Article
SR Electronic
T1 Inhibition of P-glycoprotein Activity at the Primate Blood-Brain Barrier Increases the Distribution of Nelfinavir into the Brain but Not into the Cerebrospinal Fluid
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1459
OP 1462
DO 10.1124/dmd.107.016220
VO 35
IS 9
A1 Amal Kaddoumi
A1 Sung-Up Choi
A1 Loren Kinman
A1 Dale Whittington
A1 Che-Chung Tsai
A1 Rodney J.Y. Ho
A1 Bradley D. Anderson
A1 Jashvant D. Unadkat
YR 2007
UL http://dmd.aspetjournals.org/content/35/9/1459.abstract
AB P-glycoprotein (P-gp) expression at the rodent blood-brain barrier (BBB) limits the central nervous system (CNS) distribution of anti-human immunodeficiency virus (HIV) protease inhibitors (PIs). However, it is not clear whether P-gp activity at the human BBB is as effective as that in rodents in preventing the distribution of PIs into the CNS. If it is, inhibition of P-gp at the human BBB could increase the distribution of the PIs into the CNS and, therefore, their efficacy against HIV-associated dementia. Because the distribution of the PIs into the human brain cannot be directly measured, we conducted studies in a more representative animal, the nonhuman primate. Specifically we investigated the distribution of nelfinavir (a PI and a P-gp substrate; 6 mg/kg i.v.) into the brain and cerebrospinal fluid (CSF) of nonhuman primates (cynomolgus monkeys, Macaca fascicularis) in the presence and absence of the potent and selective P-gp inhibitor, zosuquidar, and whether changes in brain nelfinavir concentration, after inhibition of P-gp, paralleled those in the CSF. Our data indicate that nelfinavir has poor penetration into the macaque's brain and CSF, and P-gp inhibition at the BBB by zosuquidar enhanced the distribution of nelfinavir into the brain by 146-fold. However, the concentration of nelfinavir in the CSF was unaffected by coadministration of zosuquidar (p > 0.05). In conclusion, P-gp inhibition at the nonhuman primate BBB significantly enhanced the distribution of nelfinavir into the brain, and this effect was not observed in the CSF. Therefore, as is common in human studies investigating P-gp inhibition at the BBB, CSF concentration of a drug should not be used as a surrogate marker for brain drug concentration. The American Society for Pharmacology and Experimental Therapeutics