Influence of genetic polymorphisms on pharmacokinetics and treatment response of mycophenolic acid: a scoping review

Abstract

This scoping review explores the impact of genetic polymorphisms on the pharmacokinetics and treatment responses of mycophenolic acid (MPA), an immunosuppressant. The study includes 83 articles from 1226 original studies, focusing on transplantation (n = 80) and autoimmune disorders (n = 3). Genetic variants in uridine 5′-diphospho-glucuronosyltransferase (UGT1A9, UGT1A8 and UGT2B7) and transmembrane transporters (ABCC2, SLCO1B1, SLCO1B3 and ABCB1) significantly affected MPA's pharmacokinetics and susceptibility to its adverse effect. Whereas variants in several genes including UGT1A9, UGT2B7, IMPDH1 and IMPDH2 have been associated with a higher risk of transplant rejection. However, there is a lack of studies on MPA's impact on autoimmune disorders and limited research on the Asian population. The findings underscore the need for further research on MPA's impact across different populations and diseases, particularly among other Asian ethnic groups, to advance personalized medicine in MPA therapy.

Executive summary

• Mycophenolic acid (MPA) is a potent immunosuppressant widely used in organ transplantation and autoimmune disorders. Its efficacy and safety are influenced by genetic variations, specifically polymorphisms in enzymes and transporters involved in MPA metabolism.

• This study reviews the influence of genetic polymorphisms to understand how genetic variations affect the pharmacokinetics and treatment efficacy of mycophenolic acid, an immunosuppressant used in transplantation and autoimmune disorders.

• This study identifies significant genetic polymorphisms in enzymes and transporters like UGT1A9, UGT2B7, IMPDH and SLCO1B1 that impact mycophenolic acid metabolism and patient response to treatment.

• Genetic variations in enzymes such as UDP-glucuronosyltransferase (UGT) and inosine monophosphate dehydrogenase (IMPDH) significantly affect MPA metabolism. For instance: UGT1A9 variants alter MPA glucuronidation, impacting drug clearance, while IMPDH 1 and 2 polymorphisms influence MPA intracellular action.

• The review points out the lack of studies on MPA's impact on autoimmune disorders and limited research involving Asian populations, emphasizing the need for more inclusive research to advance personalized medicine.

• Pharmacogenomics can guide personalized MPA dosing. Tailoring treatment based on genetic profiles optimizes drug exposure while minimizing adverse effects.

• Overall, conducting in-depth functional studies is crucial. These investigations should explore the specific consequences of genetic polymorphisms on MPA metabolism. By deciphering the intricate mechanisms at play, we can better predict drug responses and tailor treatments accordingly.

• Prospective clinical trials are essential to validate the utility of pharmacogenomic-guided dosing strategies. These trials should involve monitoring patients with varying genetic profiles and assessing their MPA treatment outcomes. Rigorous data collection will inform evidence-based recommendations.

Keywords: :

• immunosuppressant
• mycophenolic acid
• pharmacogenomics
• polymorphisms

Supplemental Material

Supplemental data for this article can be accessed at https://doi.org/10.1080/14622416.2024.2344430

Acknowledgments

The authors would like to thank to the Universiti of Malaya, Malaysia and Universitas Gadjah Mada, Indonesia for the research support.

Financial disclosure

This work was funded by SATU Joint Research Scheme Program (UM International Collaboration Grant; Project number: ST028-2023) and SATU JRS Collaboration Research Universitas Gadjah Mada Indonesia (Appointment number: 8778/UN1.P.II/Dit-Lit/PT.01.03/2023). The authors have no other 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 apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity 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.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Data availability

The present review is based on the references cited. All data generated or analyzed during the present study are included in this published article and the citations herein. Further details, opinions, and interpretation are available from the corresponding author on reasonable request.

Additional information

Funding

This work was funded by SATU Joint Research Scheme Program (UM International Collaboration Grant; Project number: ST028-2023) and SATU JRS Collaboration Research Universitas Gadjah Mada Indonesia (Appointment number: 8778/UN1.P.II/Dit-Lit/PT.01.03/2023).