Use of antiviral drugs to treat HIV infection and its consequences is often limited by the inability of the drug to access sites of infection or by drug toxicity. We are investigating the roles of specific xenobiotic transporters in the inability of HIV-1 protease inhibitors to penetrate the blood-brain barrier and in the renal toxicity of nucleoside phosphonates. To this end, we use confocal microscopy to image xenobiotic transport across isolated rat brain capillaries and choroid plexus and across killifish renal proximal tubules. With regard to poor brain penetration of HIV protease inhibitors, our experiments with brain capillaries indicate that the ATP-driven drug export pumps, p-glycoprotein and Mrp2, are important components of the blood-brain barrier and that both ritonavir and saquinavir interact with these transporters. Of the two protease inhibitors, ritonavir, has the highest affinity for both, being roughly as potent as the best inhibitors of transport yet tested. With regard to nucleoside phosphonate nephrotoxicity, both adefovir and cidofovir have been shown to be substrates for the organic anion transporter, OAT1, which is expressed in renal proximal tubule. Moreover, in model systems, nucleoside phosphonate toxicity appears to be positively correlated with cellular accumulation and with OAT1 activity. We have shown in intact renal proximal tubules that adefovir and cidofovir inhibit uptake of organic anions at the basolateral membrane mediated OAT1, but they also inhibit efflux at the luminal membrane mediated by the ATP-driven drug efflux pump, Mrp2. Since these drugs do not reduce transport mediated by luminal p-glycoprotein, they appear to interact directly with OAT1 and Mrp2 rather than inhibit metabolism. These results suggest that nucleoside phosphonates are substrates for Mrps as well as for OAT1; they raise the questions of how altered Mrp2 function might influence nephrotoxicity and how nucleoside phosphonate accumulation in renal cells might affect Mrp2 function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080060-02
Application #
6508888
Study Section
(LPC)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Hartz, Anika M S; Bauer, Bjorn; Block, Michelle L et al. (2008) Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier. FASEB J 22:2723-33
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Zhang, Wei; Dallas, Shannon; Zhang, Dan et al. (2007) Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein. Glia 55:1178-88
Bauer, Bjorn; Yang, Xiaodong; Hartz, Anika M S et al. (2006) In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. Mol Pharmacol 70:1212-9
Wang, Tongguang; Zhang, Wei; Pei, Zhong et al. (2006) Reactive microgliosis participates in MPP+-induced dopaminergic neurodegeneration: role of 67 kDa laminin receptor. FASEB J 20:906-15
Dallas, Shannon; Miller, David S; Bendayan, Reina (2006) Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol Rev 58:140-61

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