title: 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.
abstract: 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.
authors.affiliation: School of Pharmacy, Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA 98195, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
authors.forename: Sung-Up
authors.initials: SU
authors.lastname: Choi
authors.forename: Loren
authors.initials: L
authors.lastname: Kinman
authors.forename: Dale
authors.initials: D
authors.lastname: Whittington
authors.forename: Che-Chung
authors.initials: CC
authors.lastname: Tsai
authors.forename: Rodney J Y
authors.initials: RJ
authors.lastname: Ho
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D019888:Nelfinavir / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D017320:HIV Protease Inhibitors; D011804:Quinolines; C095179:zosuquidar trihydrochloride; D019888:Nelfinavir