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CYP2D6 polymorphism is not crucial for the disposition of selegiline
Author(s) -
Scheinin Harry,
Anttila Markku,
Dahl MarjaLiisa,
Karnani Hari,
Nyman Leena,
Taavitsainen Päivi,
Pelkonen Olavi,
Bertilsson Leif
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90071-6
Subject(s) - selegiline , pharmacology , dextromethorphan , methamphetamine , cyp2d6 , metabolite , pharmacokinetics , quinidine , chemistry , debrisoquine , pharmacodynamics , cytochrome p450 , medicine , metabolism , biochemistry , parkinson's disease , disease
Objective To determine the possible impact of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of selegiline. Methods Five poor metabolizers and 8 extensive metabolizers of debrisoquin (INN, debrisoquine) were given 10 mg selegiline hydrochloride. The concentrations of selegiline and its main metabolites in serum were determined for 4 days. The pharmacodynamics were quantitated by measuring platelet monoamine oxidase type B activity for 3 weeks. In addition, the effect of selegiline and its main metabolites on the CYP2D6‐catalyzed dextromethorphan O ‐demethylase activity and the effect of quinidine on the metabolism of selegiline were studied in human liver microsomes. Results Peak serum concentrations of selegiline were reached rapidly and ranged from 1 to 32 nmol/L. The metabolite concentrations were considerably higher and remained so for a longer period. There were no significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and l ‐amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration‐time curve (AUC) values of l ‐methamphetamine were, on average, 46% higher ( P = .01) in poor metabolizers than in extensive metabolizers. No significant correlations were found between debrisoquin metabolic ratio and AUC values of selegiline or its metabolites, except for l ‐methamphetamine ( r s = 0.90; P < .001). The maximum monoamine oxidase type B inhibition was 97% in both groups. The inhibitory potency of selegiline, desmethylselegiline, and l ‐methamphetamine toward dextromethorphan O ‐demethylase was very low (50% inhibitory concentration values from 160 to 580 μmol/L). Quinidine (≤100 μmol/L) did not inhibit the formation of desmethylselegiline or l ‐methamphetamine from selegiline. Conclusions CYP2D6 is not important in the primary elimination of selegiline, and the biological effect of selegiline seems to be similar in poor metabolizers and extensive metabolizers of debrisoquin. The inhibitory effect of selegiline and its main metabolites on CYP2D6 activity seems to be negligible. Clinical Pharmacology & Therapeutics (1998) 64 , 402–411; doi: