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Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline

Authors :
Pablo Zubiaur
Miriam Matas
Samuel Martín-Vílchez
Paula Soria-Chacartegui
Gonzalo Villapalos-García
Laura Figueiredo-Tor
Sofía Calleja
Marcos Navares-Gómez
Alejandro de Miguel
Jesús Novalbos
Gina Mejía-Abril
Sergio Luquero-Bueno
Manuel Román
Dolores Ochoa
Francisco Abad-Santos
Source :
Pharmaceutics, Vol 14, Iss 10, p 2001 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson’s disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (Vd/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower tmax (i.e., the time to reach the maximum concentration, Cmax) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower Cmax/DW and higher tmax (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.

Details

Language :
English
ISSN :
19994923
Volume :
14
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.990f705f9eed4cccbb456cd8e1baa53f
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics14102001