Pharmaceutics (Sep 2022)

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

  • 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

DOI
https://doi.org/10.3390/pharmaceutics14102001
Journal volume & issue
Vol. 14, no. 10
p. 2001

Abstract

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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.

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