Received for publication April 17, 2007.
Revised June 18, 2007.
Accepted for publication June 22, 2007.

Inhibition of P-gp activity at the primate blood-brain barrier increases the distribution of nelfinavir into the brain but not into the CSF

Abstract

P-glycoprotein (P-gp) expression at the rodent blood-brain barrier (BBB) limits the central nervous system (CNS) distribution of anti-HIV protease inhibitors (PIs). However, it is not clear if P-gp activity at the human BBB is as effective as 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. Since the distribution of the PIs into the human brain cannot be directly measured we conducted studies in a more representative animal, the non-human primate. Specifically we investigated the distribution of nelfinavir (a PI and a P-gp substrate; 6 mg/kg iv) into the brain and CSF of non-human primates (cynomologus monkeys, M. fascicularis) in the presence and absence of the potent and selective P-gp inhibitor, zosuquidar, and if 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 macaques' brain and CSF, and P-gp inhibition at the BBB by zosuquidar enhanced nelfinavir's distribution into the brain by 146-fold. However, nelfinavir's concentration in the CSF was unaffected by co-administration of zosuquidar (p>0.05). In conclusion, P-gp inhibition at the non-human primate BBB significantly enhanced nelfinavir's distribution 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.

Key words: ABC transporters, blood-brain barrier, blood-CNS transport, drug efflux, inhibition, multi-drug resistance, p-glycoprotein

This article has been cited by other articles:

				J. Shen, A. M. Carcaboso, K. E. Hubbard, M. Tagen, H. G. Wynn, J. C. Panetta, C. M. Waters, M. A. Elmeliegy, and C. F. Stewart Compartment-Specific Roles of ATP-Binding Cassette Transporters Define Differential Topotecan Distribution in Brain Parenchyma and Cerebrospinal Fluid Cancer Res., July 15, 2009; 69(14): 5885 - 5892. [Abstract] [Full Text] [PDF]