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

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.

Association Studies in Clinical Pharmacogenetics

“…Finally, one study with a more in vitro methodology was accepted for publication, evaluating the impact of genetic variants and mRNA on CYP1A2 function. Consistent with our association study with rasagiline [ 13 ], CYP1A2 variants showed no relationship with CYP1A2 activity. This shows that the current definition of CYP1A2 alleles is probably incorrect, and that priority should be given to the structural characterization of this gene.…”

“…Four works were accepted concerning neurodegenerative and neurodevelopmental disorders. Starting with the first type of disorders, ABCB1 rs1045642, ABCC2 rs2273697, and SLC22A1 rs34059508 were related to variability in the exposure to rasagiline, a drug used for the management of patients with Parkinson’s disease (PD) [ 13 ]. To date, no pharmacogenetic biomarker has been proposed for rasagiline or any other drug prescribed for the treatment of this disease.…”

Use of glucarpidase (carboxypeptidase‐G2) in pediatric cancer patients: 11‐year experience of a tertiary center

“…Every studied gene has already been related to methotrexate [7–9] so our descriptive study propose analyzing the genotype‐informed pharmacogenetic phenotype is a good alternative to in vitro assays to establish new gene‐enzyme interactions, particularly for old drugs like methotrexate, as previous studies of this group suggest [33, 34].…”

Investigating the Targeting Power to Brain Tissues of Intranasal Rasagiline Mesylate-Loaded Transferosomal In Situ Gel for Efficient Treatment of Parkinson’s Disease

“…However, RSM produces a neuroprotective metabolite called L-aminoindane, which in turn leads to a lower recommended therapeutic daily dose [ 10 ]. RSM was introduced into the market as oral tablets (Azilect ® ) with a single daily recommended dose of 1 mg [ 11 ]. RSM possesses reduced oral bioavailability (36%) because of the extensive first-pass metabolism [ 12 ], which affects its therapeutic efficacy.…”