Multi-Drug Transporter proteins and Protease Inhibitors

[Paul]

There has been some concern that over-expression of multi-drug transporter
proteins may lesson the effectiveness of protease inhibitor therapy. It has
also been reported that saquinavir acts as a high affinity substrate for
MDR-1 p-glycoprotein, again leading to fears that this may reduce transport
of the drug to the intracellular environment where it acts to disrupt viral
processing.

The following poster presented at the 5th Retrovirus conference in Chicago
suggests that MDR effects do not lessen the effectiveness of a range of
protease inhibitors in inhibiting HIV.

Paul Blanchard,
AIDS Treatment Project, UK.

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Anti-HIV Activities of Protease Inhibitors in T-lymphocytic Cell Lines
Overexpressing Multi-Drug Transporter Proteins.

RANGA V. SRINIVAS* & ARNOLD FRIDLAND. St. Jude Children's Research
Hospital, Memphis, TN.   

Objectives: Saquinavir, the first HIV-1 protease inhibitor approved for
human use, was recently identified as a high affinity substrate for MDR-1
Pglycoprotein (Duran et al., Clin Pharmacol Ther, 61, N°2, p193, 1997). To
determine whether over-expression of multi-drug transporter proteins can
lead to treatment failures with HIV-1 protease inhibitors, we investigated
the antiviral emcacy of different protease inhibitors in vitro, in cell
lines over-expressing various transporters.    
Methods: A p24 yield reduction assay was used to determine the antiviral
activity of the compounds. The protease inhibitors saquinavir, ritonavir,
indinavir, and nelfinavir were tested in CEM-VLB100 (expressing MDR-1),
CEM-VMI (expressing MRP-1), or CEM-rl which was selected for
PMEA-resistance, and expresses a novel efflux pump unrelated to MDR-1 or
MRP-1. MT-2 cells transfected with control vector (pcDNA3), or an MDR-1
expression vector were also tested.   
Results: No significant differences in the antiviral activity of
saquinavir, or other protease inhibitors were observed between cell lines
over-expressing the various multi-drug transporters, and corresponding
controls. By comparison, the antiviral emcacy of AZT was appreciably
reduced in cell lines over-expressing MDR-1, and PMEA-resistant CEM-r1
cells.   
Conclusions: Over-expression of different multi-drug transporter proteins
in target cells does not reduce antiviral efficacy of protease inhibitors.

Ref: RANGA V. SRINIVAS* & ARNOLD FRIDLAND, Anti-HIV Activities of Protease
Inhibitors in T-lymphocytic Cell Lines Overexpressing Multi-Drug
Transporter Proteins. Abstract 403. 5th Conference on Retroviruses and
Opportunistic Infections, Feb 1-5, 1998, Chicago, IL.