Rasagiline Pharmacokinetics in CYP1A2 Variant Healthy Smokers & Non-smokers in Different Doses

Abstract

Objectives: Rasagiline, a drug for Parkinson’s disease is metabolized by CYP1A2 enzyme. The objective of the study was to investigate the influence of cytochrome P450 1A2 variants and smoking status of healthy individuals on the pharmacokinetics of rasagiline.
 Methods: A comparative, open label, interventional, single oral dose, pharmacokinetic study was performed on 108 healthy volunteers in UHS & UVAS, Lahore. Data collection was initiated in June 2016 and ended in January 2018. It was divided in three phases with 1, 2 and 5mg of rasagiline given to a group of 36 volunteers in each phase. Volunteers were sub-divided into six groups of AA smokers, AA non-smokers, AC smokers, AC non-smokers, CC smokers & CC non-smokers on the basis of genotyping and smoking status. Serial blood sampling was performed at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 & 12 hours after administration of rasagiline tablets. Plasma concentrations were determined using High Performance Liquid Chromatography (HPLC) method. Pharmacokinetic (PK) parameters were calculated using software (APO) pharmacological analysis.
 Results: Analysis of variance (ANOVA) showed significant difference between AA and CC groups. Multiple group comparison with post hoc Tukey’s revealed that AA-smokers had significantly less tmax (p<0.001), t1/2 (p<0.012), AUC (p<0.008) and highest Cl (p<0.001) as compared to CC-smokers. The trend was same across all three doses.
 Conclusion: The study concludes that the systemic metabolism of rasagiline is significantly increased in CYP1A2*AA variants while smoking status did not show consistent difference in PK parameters.
 Registered Trial: ISRCTN68198254
 doi: https://doi.org/10.12669/pjms.38.3.4940
 How to cite this:Bilal R, Ahmad NS, Zaffar S, Mazhar MU, Siddiqui WA, Tariq S. Rasagiline Pharmacokinetics in CYP1A2 Variant Healthy Smokers & Non-smokers in Different Doses. Pak J Med Sci. 2022;38(3):---------. doi: https://doi.org/10.12669/pjms.38.3.4940
 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

“…A correct definition of CYP1A2 will allow to evaluate whether it is a useful biomarker in rasagiline treatment. In the previously cited paper evaluating CYP1A2 -163C>A as the tagging SNP for *1F [ 8 ], authors conclude on the impact of this variant. However, this variant occurs in haplotypes together with other quite prevalent variants, defining alleles other than *1F (the allele containing the −163C>A variant only) (i.e., *1G-*1N) ( Table 1 ).…”

“…Scarce pharmacogenetic research on rasagiline has been published to date. A recent paper evaluated the impact of the CYP1A2 -163C>A variant on rasagiline pharmacokinetics [ 8 ]. However, this variant appears in several alleles and the impact of each allele or haplotype may be different.…”