J. Pharm. Pharmacogn. Res., vol. 11, no. 6, pp. 934-952, Nov-Dec 2023.

DOI: https://doi.org/10.56499/jppres23.1686_11.6.934

Review

SLCO1B1 and CYP3A4 allelic variants associated with pharmacokinetic interactions and adverse reactions induced by simvastatin and atorvastatin used in Peru: Clinical implications

[Variantes alélicas de SLCO1B1 y CYP3A4 asociadas a interacciones farmacocinéticas y reacciones adversas inducidas por simvastatina y atorvastatina usadas en el Perú: Implicaciones clínicas]

Angel T. Alvarado^1*, Ana María Muñoz², Roberto O. Ybañez-Julca³, Mario Pineda-Pérez⁴, Nesquen Tasayco-Yataco⁵, María R. Bendezú⁶, Jorge A. García⁶, Felipe Surco-Laos⁶, Haydee Chávez⁶, Doris Laos-Anchante⁶, Aura Molina-Cabrera⁶, Carmela Ferreyra-Paredes⁶, Nelly Vega-Ramos⁶, Patricia Castillo-Romero⁶, Javier Chávez-Espinoza⁶, Juan Panay-Centeno⁶, Eliades Yarasca-Carlos⁷

¹International Research Unit in Molecular Pharmacology and Genomic Medicine (UNIPHARMAGEM), VRI San Ignacio de Loyola University, La Molina 15024, Lima, Peru.

²Institute of Food Science and Nutrition, ICAN, San Ignacio de Loyola University, La Molina 15024, Lima, Peru.

³Faculty of Pharmacy and Biochemistry, National University of Trujillo, 13006, Trujillo, Peru.

⁴Pharmacy and Biochemistry, Faculty of Health Sciences, Scientific University of the South, UCSUR, 15067, Lima, Peru.

⁵Human Medicine, Norbert Wiener University, 15046, Lima, Peru.

⁶Faculty of Pharmacy and Biochemistry, San Luis Gonzaga National University of Ica, 11004, Ica, Peru.

⁷Biological Sciences Faculty, San Luis Gonzaga National University of Ica, 11001, Ica, Peru.

*E-mail: angel.alvaradoy@usil.pe

Abstract

Context: Statins reduce the risk of stroke and prevent cardiac events in people with atherosclerosis and diabetes mellitus; and could affect the proliferation, migration, and survival of cancer cells.

Aims: To review the most up-to-date and available scientific evidence on the allelic variants of SLCO1B1 and CYP3A4 associated with pharmacokinetic interactions and adverse reactions induced by simvastatin and atorvastatin used in Peru, and their clinical implications.

Methods: The bibliographic search was carried out in the PubMed/Medline, Google Scholar and Science Direct databases. The keywords were: “statin”, “atorvastatin”, “simvastatin” in combination with “pharmacokinetics”, “pharmacogenetics”, “CYP3A4”, “SLCO1B1” or “drug interactions” considering the eligibility criteria defined by the PRISMA-2020 international statement.

Results: Scientific evidence indicates a significant association between SLCO1B1 rs4149056 c.521T>C (521CC and 521TC) and increased plasma levels, area under the plasma concentration curve (AUC) and maximum plasma concentration (C_max) of simvastatin, compared to wild-type SLCO1B1*1/*1 521TT (p<0.05). SLCO1B1 521C is not associated with atorvastatin (p>0.05). Patients with SLCO1B1 521CC had a significantly higher risk of myopathy and rhabdomyolysis induced by simvastatin compared to TT (p<0.05). An association was also found between CYP3A4*1/*22/CYP3A4*3/*22 and increased pharmacokinetic parameters of simvastatin compared to CYP3A4*1/*1 (p< 0.05).

Conclusions: Based on the review of the published scientific evidence, it is concluded that individuals carrying the allelic variants SLCO1B1 (c.521T>C), CYP3A4*1/*22 and CYP3A4*3/*22 could be associated with an increase in the pharmacokinetic parameters and with an increased risk of myopathy and rhabdomyolysis induced by simvastatin, and not by atorvastatin.

Keywords: adverse reactions; atorvastatin; CYP3A4; pharmacokinetic interactions; SLCO1B1; simvastatin.

Resumen

Contexto: Las estatinas reducen el riesgo accidente cerebrovascular y previene los eventos cardíacos en personas con aterosclerosis y diabetes mellitus; y podría afectar la proliferación, migración y supervivencia de las células cancerosas.

Objetivos: Revisar la evidencia científica más actualizada y disponible sobre las variantes alélicas de SLCO1B1 y CYP3A4 asociadas a interacciones farmacocinéticas y reacciones adversas inducidas por la simvastatina y atorvastatina usadas en el Perú, y sus implicaciones clínicas.

Métodos: Se realizó la búsqueda bibliográfica en bases de datos PubMed/Medline, Google Scholar and Science Direct databases. Las palabras clave fueron: “estatina”, “atorvastatina”, “simvastatina” en combinación con “farmacocinética”, “farmacogenética”, “CYP3A4”, “SLCO1B1” o “interacciones con fármacos” teniendo en cuenta los criterios de elegibilidad definidos por la declaración internacional PRISMA-2020.

Resultados: La evidencia científica indica asociación significativa entre SLCO1B1 rs4149056 c.521T>C (521CC y 521TC) y el aumento de los niveles plasmáticos, del área bajo la curva de concentraciones plasmáticas (AUC) y concentración plasmática máxima (C_max) de simvastatina, respecto al wild-type SLCO1B1*1/*1 521TT (p<0.05). SLCO1B1 521C no está asociado con atorvastatina (p>0.05). Los pacientes con SLCO1B1 521CC presentaron mayor riesgo significativo de miopatía y rabdomiólisis inducida por simvastatina frente a TT (p< 0.05). También se encontró asociación entre CYP3A4*1/*22/CYP3A4*3/*22 y aumento de los parámetros farmacocinéticos de simvastatina en comparación con CYP3A4*1/*1 (p < 0.05).

Conclusiones: Basado en la revisión de la evidencia científica publicada se concluye que los individuos portadores de las variantes alélicas SLCO1B1 (c.521T>C), CYP3A4*1/*22 y CYP3A4*3/*22 podrían estar asociados a un incremento de los parámetros farmacocinéticos y con un mayor riesgo de miopatía y rabdomiólisis inducida por simvastatina, y no por atorvastatina.

Palabras Clave: atorvastatina; CYP3A4; interacciones farmacocinéticas; reacción adversa; SLCO1B1; simvastatina.

Citation Format: Alvarado AT, Muñoz AM, Ybañez RO, Pineda M, Tasayco N, Bendezú G, García JA, Surco F, Chávez H, Laos D, Molina A, Ferreyra C, Vega N, Castillo P, Chávez J, Panay J, Yarasca E (2023) SLCO1B1 and CYP3A4 allelic variants associated with pharmacokinetic interactions and adverse reactions induced by simvastatin and atorvastatin used in Peru: Clinical implications. J Pharm Pharmacogn Res 11(6): 934–952. https://doi.org/10.56499/jppres23.1686_11.6.934

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