Modulation of Tenofovir by Probenecid: Impact on Drug, Interleukin-1β, and Dopamine Concentration in the Prefrontal Cortex and Cerebellum

Abstract

The blood-brain barrier's limited permeability to tenofovir restricts its ability to clear HIV from the brain. Probenecid acting as an adjuvant increases tenofovir concentrations in plasma and the kidneys thereby enhancing its therapeutic effect. However, the probenecid effect on brain tenofovir concentration and possible adverse effects remains poorly understood. We investigated the effect of probenecid co-administered tenofovir on tenofovir brain concentration, interleukin-1β (IL-1β) and dopamine concentration in the prefrontal cortex (PFC) and the cerebellum. Ninety-six male BALB/c mice were divided into four groups viz: a control group, Tenofovir disoproxil fumarate (TDF) treated, probenecid treated, and TDF + probenecid treated. We orally administered a single dose of TDF (5mg/kg), and probenecid (8.3mg/kg), and sacrificed six mice per group after 1h, 4h, and 6h post-treatment to collect plasma, PFC, and cerebellar tissue. Co-administered tenofovir increased tenofovir concentration, peaking at 6h with the cerebellum having the highest concentration. This suggests that probenecid enhanced the entry of tenofovir into the brain. Tenofovir alone increased IL-1β concentration at all intervals post-administration, while probenecid alone had no impact on IL-1β concentration. Co-administered tenofovir also increased IL-1β concentration. Probenecid's limited impact on IL-1β concentration following co-administration suggests that its anti-inflammatory properties may require more than 6h to have an effect. Furthermore, neither tenofovir nor probenecid affected dopamine concentration. In conclusion, probenecid enhances the concentration and retention of tenofovir in the brain, making it a possible pharmacokinetic enhancer. However, its anti-inflammatory effects may require a longer duration to fully manifest.

Note:
Funding declaration: This work was supported by the University of KwaZulu Natal, College of health Sciences.

Conflict of Interests: The authors declare that they have no competing interests.

Ethical Approval: All animal experimentation was approved by the Animal Research Ethics Committee of the University of KwaZulu-Natal (AREC/00003133/2021).

Keywords: Tenofovir, Probenecid, Plasma, brain, Interleukin-1β, Dopamine