Selegiline pharmacokinetics are unaffected by the CYP3A4 inhibitor itraconazole.
OBJECTIVE
To characterise the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of selegiline in healthy volunteers.


METHODS
In this randomised, placebo-controlled crossover study with two phases, 12 healthy volunteers took either 200 mg itraconazole or matched placebo once daily for 4 days. On day 4, a single 10-mg oral dose of selegiline hydrochloride was administered. Serum concentrations of selegiline and its primary metabolites desmethylselegiline and l-methamphetamine were determined up to 32 h. A caffeine test was performed on day 3 of both phases, by measuring the plasma paraxanthine/caffeine concentration ratio 6 h after caffeine intake, to examine the role of CYP1A2 in selegiline pharmacokinetics. In addition, the effects of itraconazole on the metabolism of selegiline in vitro were characterised by using human liver microsomes.


RESULTS
Itraconazole had no significant effects on the pharmacokinetic variables of selegiline, desmethylselegiline or l-methamphetamine, with the exception that the AUC of desmethylselegiline was increased by about 10% (P < 0.05). There was a significant correlation between the AUC(desmethylselegiline)/AUC(selegiline) ratio and the paraxanthine/caffeine ratio (r = 0.41; P < 0.05), suggesting involvement of CYP1A2 in the formation of desmethylselegiline. In experiments with human liver microsomes, itraconazole had no inhibitory effect on the formation of either desmethylselegiline or l-methamphetamine from selegiline.


CONCLUSIONS
The pharmacokinetics of selegiline in healthy volunteers were unaffected by the potent CYP3A4 inhibitor itraconazole. In addition, itraconazole showed no inhibitory effect on the biotransformation of selegiline to desmethylselegiline and l-methamphetamine by human liver microsomes. These findings suggest that selegiline is not susceptible to interaction with CYP3A4 inhibitors.
Kivistö
K T
KT
Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, 00290 Helsinki, Finland. kari.kivisto@hus.fi
Wang
J S
JS
Backman
J T
JT
Nyman
L
L
Taavitsainen
P
P
Anttila
M
M
Neuvonen
P J
PJ
D000328:Adult; D000662:Amphetamines / Q000097:blood / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D000697:Central Nervous System Stimulants / Q000097:blood / Q000493:pharmacokinetics; D016001:Confidence Intervals; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000097:blood / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012642:Selegiline / Q000097:blood / Q000493:pharmacokinetics*; D018709:Statistics, Nonparametric
D000662:Amphetamines; D000935:Antifungal Agents; D000697:Central Nervous System Stimulants; D065607:Cytochrome P-450 Enzyme Inhibitors; D012642:Selegiline; D017964:Itraconazole; D008694:Methamphetamine; C017861:desmethylselegiline; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human