Induction effect of antiretroviral bictegravir on the expression of Abcb1, Abcg2 and Abcc1 genes associated with P-gp, BCRP and MRP1 transporters present in rat peripheral blood mononuclear cells

ABSTRACT

Background

Antiretrovirals have the potential to cause drug interactions leading to inefficacy or toxicity via induction of efflux transporters through nuclear receptors, altering drug concentrations at their target sites.

Research Design and Methods

This study used molecular dynamic simulations and qRT-PCR to investigate bictegravir’s interactions with nuclear receptors PXR and CAR, and its effects on efflux transporters (P-gp, BCRP, MRP1) in rat PBMCs. PBMC/plasma drug concentrations were measured using LC-MS/MS to assess the functional impact of transporter expression.

Results

Bictegravir significantly increased the expression of ABC transporters, with Car identified as a key mediator. This suggests that bictegravir’s influence on nuclear receptors could affect drug transport and efficacy at the cellular level.

Conclusions

Bictegravir activates nuclear receptors enhancing efflux transporter expression. Understanding these interactions is crucial for preventing drug–drug interactions and reducing toxicity in clinical use. Combining CAR antagonists with bictegravir may prevent drug resistance and toxicity. However, these findings are based on preclinical data and necessitate further clinical trials to confirm their applicability in clinical settings.

KEYWORDS:

• Bictegravir
• efflux transporters and nuclear receptors
• toxicity, drug resistance, and drug interaction
• PBMCs
• intracellular bioavailability

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We are thankful to NIPER-Ahmedabad and the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India for all their support required for this research.

Data availability statement

Data can be available on request.

Author contributions statement

T Jadav contribution: Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft.

N Rajput contribution: Formal analysis, Methodology, Validation.

H Kumar contribution: Formal analysis, Methodology, Validation, Supervision.

S Kumar Behera contribution: Formal analysis, Investigation, Supervision, Visualization.

P Sengupta contribution: Conceptualization, Investigation, Project administration, Supervision, Visualization, Writing – review & editing.

Additional information

Funding

This paper was not funded.