Cocaine Modulates CPY3A4 in Primary Human Macrophages in a Donor-Specific Fashion

Abstract ID 96967 Poster Board 126 CYP3A4 metabolizes 60% of therapeutic drugs, including antiretroviral therapies (ART). CYP3A4 also contributes to cocaine metabolism. People living with HIV that also consume illicit substances have poor virologic control, despite access to ART. While this is likely attributable to lack of adherence, we hypothesize adverse drug-drug interactions also contribute to loss of virologic suppression. To evaluate this, we obtained peripheral blood mononuclear cells from healthy donors and differentiated them into monocyte-derived macrophages (MDM) that were treated with cocaine 10 uM cocaine for 24 hours. While CYP3A4 was expressed in primary human MDM, interdonor variability occurred. Interestingly, cocaine caused a dichotomous response wherein it significantly increased CYP3A4 for some donors, whom we termed "responders". However, "non-responders" were resistant to this effect and exhibited no change or even a decrease following cocaine treatment. CYP3A4 enzymatic activity confirmed the dichotomous response. The mechanism behind the dichotomous response was not related to CYP3A4 polymorphisms, plasma cytokines, cytokines in cell supernatant, or sex. However, we determined that CYP3A4's primary transcription factor, PXR, contributed to cocaine's effect as there was a similar dichotomous response in its expression. Cocaine had no effect on CAR, another CYP3A4 regulator. Our data suggest that some individuals are vulnerable to adverse drug-drug interactions with ART and cocaine that may result in higher viral load.