Factors Affecting CYP3A-Mediated Metabolism of Drugs of Abuse in HIV+ Patients

Tufts University Boston, Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): HIV+ patients are often faced with an emotional burden resulting in depression and sleep disturbances for which they seek prescription medicines, such as benzodiazepines. Benzodiazepines, however, are known drugs of abuse and taking them could lead to the development of drug addiction in the HIV+ patient population. Drug addiction is a major problem in the HIV+ population and efforts to decrease the likelihood of abuse are needed. Benzodiazepines are primarily metabolized by the major class of the cytochrome P450 (CYP) family, CYP3A, which exhibits wide inter-individual variability and is inhibited or induced by many currently marketed drugs, including medications used to treat HIV. Factors that inhibit CYP3A activity could thereby enhance benzodiazepine plasma levels and increase their physical dependence potential and toxicity. Here, we propose to study two factors that may affect CYP3A activity: concurrent medication and genetic polymorphisms. Since the effect of chronic administration of the protease inhibitor, ritonavir, on CYP3A activity in HIV+ patients is currently unclear, we propose to study the effect of long-term ritonavir therapy on CYP3A metabolic activity using the CYP3A specific probe drug, midazolam, in HIV+ subjects. The results from this study will provide important information on the potential for ritonavir to decrease CYP3A activity and thus elevate plasma levels of any concurrent medications the HIV+ individual is taking, such as benzodiazepines resulting in increased drug addiction or toxicity. Our long term goal is to provide information that could be used by physicians to help guard HIV+ patients from potentially unsafe drug-drug interactions and prevent benzodiazepine dependence. CYP3A activity could also be affected by genetic variants in the gene itself, or a known regulator, the pregnane X receptor (PXR). Previous work has focused on the promoter and coding regions of the above genes, leaving the 3'untranslated region (3'UTR) largely unexplored. The 3'UTR plays an important role in genetic regulation and polymorphisms could have significant effects on gene expression and metabolic activity. We, therefore, propose to study the effect of our laboratory's previously identified genetic polymorphisms in the 3'UTR of PXR on midazolam CYP3A- mediated metabolism using several different sources of in vitro and in vivo CYP3A activity, including HIV+ individuals. Further exploration into the exact mechanism by which the PXR genetic variants may be affecting CYP3A activity will also be explored. Investigation into the factors affecting the body's ability to metabolize drugs of abuse is essential in order to help prevent patients from becoming addicted, especially HIV+ individuals who are often taking potential drugs of abuse for therapeutic reasons. [unreadable] [unreadable] [unreadable]