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The Brain Entry of HIV-1 Protease Inhibitors Is Facilitated When Used in Combination

Marzolini, Catia and Mueller, Rita and Li-Blatter, Xiaochun and Battegay, Manuel and Seelig, Anna. (2013) The Brain Entry of HIV-1 Protease Inhibitors Is Facilitated When Used in Combination. Molecular pharmaceutics, Vol. 10, H. 6 , S. 2340–2349.

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Official URL: http://edoc.unibas.ch/dok/A6135376

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Abstract

One hypothesis for persisting HIV-associated neurocognitive disorders (HAND) in effectively treated individuals is the limited permeation of antiretroviral agents (ARV) across the blood-brain barrier (BBB). However, the physicochemical factors limiting the brain entry of a given ARV and the mutual interactions of combined drugs on their brain entry have not been properly characterized. Using transporter kinetic measurements, we show that large lipophilic drugs such as protease inhibitors (PI) have strong binding affinities to drug efflux transporters expressed at the BBB and thus are prevented from entering the brain. However, when combined, the PI with the highest binding affinity (i.e., boosting ritonavir) will occupy a large proportion of the transporter binding sites and thus slow down the efflux rate of the coadministered PI thereby facilitating its brain entry. Furthermore, using thermodynamic measurements and computational modeling, we show that ARV with small cross-sectional areas (AD > 70 Å(2)) and octanol-water distribution coefficients (-1 > log D >5) such as most nucleoside analogues have a high passive influx and cross the BBB despite interactions with drug transporters. These data indicate that HIV therapies combining small diffusing molecules with large lipophilic molecules are better suited for brain entry and should be preferred for HAND. This work highlights the role of PI as modulators of drugs' brain entry.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biophysical Chemistry (Seelig A)
UniBasel Contributors:Seelig-Löffler, Anna
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:1543-8384
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:21 Jun 2013 12:29
Deposited On:21 Jun 2013 12:28

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