Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids.
OBJECTIVE
The purpose of this study was to characterize the dose relationship of selegline and desmethylselegiline pharmacokinetics within the selegiline dose range from 5 to 40 mg.


METHODS
Eight female subjects, of whom four were using oral contraceptives, ingested a single dose of 5 mg, 10 mg, 20 mg or 40 mg of selegiline HCl in an open four-period randomized study. Concentrations of selegiline and desmethlylselegiline in serum were measured by gas chromatography for 5 h. As it became evident that the use of oral steroids had a drastic effect on selegiline concentrations, the pharmacokinetic analyses were performed separately for oral contraceptive users and those not receiving any concomitant medication.


RESULTS
The total AUC and Cmax of selegiline were 10-to 20-fold higher in those subjects taking oral steroids compared with subjects with no concomitant medication; this finding was consistent and statistically significant at all the four dose levels. The dose linearity of selegiline pharmacokinetics failed to be demonstrated in both groups. The AUC and Cmax of desmethylselegiline were only moderately higher (about 1.5-fold; P=NS at each dose level) in the subjects taking oral steroids than in those not receiving concomitant medication. The AUC values of desmethylselegiline increased in a dose linear manner in subjects with no concomitant medication, but not in the oral steroid group. The metabolic ratio (AUC(desmethylselegiline)/AUC(selegiline)) was several-fold lower in the group receiving oral steroids compared with the no-concomitant-medication group (P<0.005 at all the four dose levels).


CONCLUSIONS
Concomitant use of oral contraceptives caused a drastic (20-fold) increase in the oral bioavailability of selegiline. The highly significant difference in the metabolic ratio between the groups provides evidence that the mechanism of the interaction between selegiline and female sex steroids involves reduced T-demethylation of selegiline. The present results suggest that concomitant use of selegiline with exogenous female sex steroids should be avoided or the dosage of selegiline should be reduced in order to minimize the risks of selegiline related adverse drug reactions.
Laine
K
K
Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland.
Anttila
M
M
Helminen
A
A
Karnani
H
H
Huupponen
R
R
D000284:Administration, Oral; D000328:Adult; D000662:Amphetamines / Q000097:blood; D000978:Antiparkinson Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D012642:Selegiline / Q000097:blood / Q000493:pharmacokinetics*
D000662:Amphetamines; D000978:Antiparkinson Agents; D003271:Contraceptive Agents, Female; D012642:Selegiline; C017861:desmethylselegiline