The potential for probenecid to have a serious interaction with HIV-1 protease inhibitors

Stephen Taylor, for HIV i-Base

Marten Huisman from the Netherlands Cancer Institute [1] presented a basic science paper concerning the stimulation of the multidrug resistance protein (MRP2) by probenecid. However, this work may have important clinical implications in a ways he had not envisaged.

MRP2 is a glycoprotein found in the gut wall of humans and animals. Previous work by Huisman and colleagues has demonstrated the protease inhibitors ritonavir (RTV, Norvir), saquinavir (SQV, Fortovase) and indinavir (IDV, Crixivan) are substrates for MRP2 and that other drugs including probenecid can stimulate this protein. In the paper presented probenecid was being used to see if the reduced oral bioavailability of SQV fed to PGP deficient mice may be attributable to stimulation of MRCP2. Briefly, he found that co administration of probenecid and SQV to PGP deficient mice reduced the AUC of radiolabled SQV by 12 and 14 fold respectively.

However, during the course of his talk it became apparent to certain clinicians and pharmacists in the audience that the potential of probenecid to prevent RTV uptake may have profound consequences for protease inhibitor receiving patients treated for syphilis. The hypothesis runs something like this: if an HIV-1-positive person receiving Kaletra (lopinavir (LPV) and ritonavir (RTV) in combination) acquires syphilis, he/she is then likely to be treated with a one to two week course of probenecid as an adjunct to his/her penicillin. If probenecid does interfere with RTV absorption (as yet unproven in humans in vivo) then essentially LPV concentrations may fall to near zero without the boosting effect of RTV. The consequences are obvious. A probenecid and protease inhibitor interaction study is urgently needed!


Probenecid is unlikely to be the only pharmaceutical with action on MRP2, for instance, it is known that fibrates induce MDR-2 gene expression in the mouse. Perhaps even food substances may influence these proteins or genes in a similar way that garlic has been found to affect PGP expression.

Some of these factors may be contributing to the observed interindividual variations in ARVs found with TDM. It should also be noted that MDR-2/3 is involved in phospholipid transport in the liver and may also have some part to play in the disturbances of trigylceride and cholesterol metabolism seen after ARV initiation.

A summary article on the role and manipulation of MDR in the setting of cancer chemotherapy is available with free full text at:;95/4/255


  1. Huisman M, Crommentuyn HR, Rosing H et al. Co-administration of multidrug resistance protein 2 (MRP2)- stimulators dramatically reduces saquinavir oral availability Abs 6 : P 2.3

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