CYP2C19 polymorphism is not important for the in vivo metabolism of selegiline

Objectives: To address the relevance of cytochrome P-450 (CYP) 2C19 polymor phism for the pharmacokinetics and dynamics of selegiline and its two known primary metabolites, desmethylselegiline and 1-methamphetamine. Methods: Six extensive (mephenytoin S/R ratio <0.3; EM) and six poor (mephe nytoin S/R ratio >0.8; PM) hydroxylators of S-mephenytoin ingested a single 10-mg oral dose of selegiline hydrochloride. Serum concentrations of seleg iline, desmethylselegiline and l-methamphetamine were measured by gas chrom atography mass spectrometry for up to 48 h. In addition, the platelet monoa mine oxidase type B (MAO-B) activity was measured for 14 days to describe p ossible differences in the pharmacodynamics of selegiline and its metabolit es between EM and PM. Results: The CYP2C19 phenotype had no significant effects on the pharmacoki netic variables of selegiline. PM of S-mephenytoin had 68% higher mean AUC of desmethylselegiline (P=0.0017) than EM, but no significant differences w ere observed in other pharmacokinetic parameters of desmethylselegiline. Co ntrary to desmethylselegiline, the serum 1-methamphetamine concentrations w ere slightly lower in PM, but no statistically significant differences were observed in l-methamphetamine pharmacokinetics between the two CYP2C19 phe notypes. Accordingly, the magnitude of MAO-B inhibition showed no significa nt differences between the study groups. Conclusions: CYP2C19 polymorphism does not seem to be crucial for the metab olism or clinical effects of selegiline.