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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.674117

DOI=10.3389/fphar.2021.674117

ISSN=1663-9812

ABSTRACT=<p>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 <italic>CYP3A4</italic>, <italic>CYP3A5</italic>, <italic>MDR1</italic> and <italic>POR</italic> 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 <italic>TaqMan</italic>® probes, we determined the allelic frequency of seven variants in <italic>CYP3A4</italic>, <italic>CYP3A5</italic>, <italic>MDR1</italic> and <italic>POR</italic> 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 (C<sub>0</sub>/D and C<sub>2</sub>/D) at specific time points post-transplant. We found that <italic>CYP3A5*3/*3</italic> carriers required lower doses of TAC. In TAC treated patients, most <italic>CYP3A5*3/*3</italic> carriers presented higher C<sub>0</sub>/D and a high proportion of patients with C<sub>0</sub> levels outside the therapeutic range relative to other genotypes. These results reinforce the value of considering <italic>CYP3A5</italic> genotypes alongside therapeutic drug monitoring for TAC treated Chilean kidney recipients.</p>