Frontiers in Pharmacology (Dec 2021)

Effect of CYP3A4, CYP3A5, MDR1 and POR Genetic Polymorphisms in Immunosuppressive Treatment in Chilean Kidney Transplanted Patients

  • Stephania Contreras-Castillo,
  • Anita Plaza,
  • Jana Stojanova,
  • Jana Stojanova,
  • Gustavo Navarro,
  • Rodolfo Carmona,
  • Fernando Corvalán,
  • Leslie Cerpa,
  • Leslie Cerpa,
  • Christopher Sandoval,
  • Daniel Muñoz,
  • Marina Leiva,
  • Luis E. Castañeda,
  • Nayaret Farias,
  • Carolina Alvarez,
  • Gabriel Llull,
  • Sergio Mezzano,
  • Leopoldo Ardiles,
  • Nelson Varela,
  • Nelson Varela,
  • María S. Rodríguez,
  • Claudio Flores,
  • Juan Pablo Cayún,
  • Juan Pablo Cayún,
  • Paola Krall,
  • Paola Krall,
  • Luis A. Quiñones,
  • Luis A. Quiñones

DOI
https://doi.org/10.3389/fphar.2021.674117
Journal volume & issue
Vol. 12

Abstract

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Cyclosporine (CsA) and tacrolimus (TAC) are immunosuppressant drugs characterized by a narrow therapeutic range and high pharmacokinetic variability. The effect of polymorphisms in genes related to the metabolism and transport of these drugs, namely CYP3A4, CYP3A5, MDR1 and POR genes, has been evaluated in diverse populations. However, the impact of these polymorphisms on drug disposition is not well established in Latin American populations. Using TaqMan® probes, we determined the allelic frequency of seven variants in CYP3A4, CYP3A5, MDR1 and POR in 139 Chilean renal transplant recipients, of which 89 were treated with CsA and 50 with TAC. We tested associations between variants and trough and/or 2-hour concentrations, normalized by dose (C0/D and C2/D) at specific time points post-transplant. We found that CYP3A5*3/*3 carriers required lower doses of TAC. In TAC treated patients, most CYP3A5*3/*3 carriers presented higher C0/D and a high proportion of patients with C0 levels outside the therapeutic range relative to other genotypes. These results reinforce the value of considering CYP3A5 genotypes alongside therapeutic drug monitoring for TAC treated Chilean kidney recipients.

Keywords