SLCO1B1 and ABCG2 genotype‐informed phenotypes are related to variation in ramipril exposure

Author:

Abbes Houwaida123ORCID,Zubiaur Pablo1,Soria‐Chacartegui Paula1,de la Torre Tamara1,Villapalos‐García Gonzalo1,Candau Carmen1,Rodríguez‐Lopez Andrea1,González‐Iglesias Eva1,Aldama Marina1,Navares‐Gomez Marcos1,Omezzine Asma23,Ochoa Dolores1,Abad‐Santos Francisco14ORCID

Affiliation:

1. Clinical Pharmacology Department Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP) Madrid Spain

2. Biochemistry Department, LR12SP11 Sahloul University Hospital Sousse Tunisia

3. Faculty of Pharmacy of Monastir University of Monastir Monastir Tunisia

4. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) Instituto de Salud Carlos III Madrid Spain

Abstract

AbstractRamipril is an angiotensin‐converting enzyme inhibitor used for hypertension and heart failure management. To date, scarce literature is available on pharmacogenetic associations affecting ramipril. The goal of this study was to investigate the effect of 120 genetic variants in 34 pharmacogenes (i.e., genes encoding for enzymes like CYPs or UGTs and transporters like ABC or SLC) on ramipril pharmacokinetic variability and adverse drug reaction (ADR) incidence. Twenty‐nine healthy volunteers who had participated in a single‐dose bioequivalence clinical trial of two formulations of ramipril were recruited. A univariate and multivariate analysis searching for associations between genetic variants and ramipril pharmacokinetics was performed. SLCO1B1 and ABCG2 genotype‐informed phenotypes strongly predicted ramipril exposure. Volunteers with the SLCO1B1 decreased function (DF) phenotype presented around 1.7‐fold higher dose/weight‐corrected area under the curve (AUC/DW) than volunteers with the normal function (NF) phenotype (univariate p‐value [puv] < 0.001, multivariate p‐value [pmv] < 0.001, β = 0.533, R2 = 0.648). Similarly, volunteers with ABCG2 DF + poor function (PF) phenotypes presented around 1.6‐fold higher AUC/DW than those with the NF phenotype (puv = 0.011, pmv < 0.001, β = 0.259, R2 = 0.648). Our results suggest that SLCO1B1 and ABCG2 are important transporters to ramipril pharmacokinetics, and their genetic variation strongly alters its pharmacokinetics. Further studies are required to confirm these associations and their clinical relevance.

Funder

Universidad Autónoma de Madrid

Instituto de Salud Carlos III

European Social Fund Plus

Publisher

Wiley

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