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

详细信息    查看全文

• 作者：Catia Marzolini ; Rita Mueller ; Xiaochun Li-Blatter ; Manuel Battegay ; Anna Seelig
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：June 3, 2013
• 年：2013
• 卷：10
• 期：6
• 页码：2340-2349
• 全文大小：433K
• 年卷期：v.10,no.6(June 3, 2013)
• ISSN：1543-8392

文摘

One hypothesis for persisting HIV-associated neurocognitive disorders (HAND) in effectively treated individuals is the limited permeation of antiretroviral agents (ARV) across the blood鈥揵rain 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 (A_D < 70 脜²) and octanol鈥搘ater distribution coefficients (鈭? < 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鈥?brain entry.

Keywords:

HIV; brain permeation; antiretroviral drugs; P-glycoprotein; BCRP; neurocognitive disorders