The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel.
OBJECTIVE
Our objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3-keto-desogestrel after administration of desogestrel, by using the selective inhibitors fluconazole (CYP2C) and itraconazole (CYP3A4).


METHODS
This study had a three-way crossover design and included 12 healthy females, the data from 11 of whom were analyzed. In the first (control) phase all subjects received a single 150 microg oral dose of desogestrel alone. In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a randomized balanced order. Desogestrel was given 1 h after the last dose of the CYP inhibitor. Plasma 3-keto-desogestrel concentrations were determined for up to 72 h post dose.


RESULTS
Pretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration-time curve (AUC) of 3-keto-desogestrel by 72.4% (95% confidence interval on the difference 12%, 133%; P = 0.024) compared with the control phase, whereas fluconazole pretreatment had no significant effect (95% CI on the difference -42%, 34%). Neither enzyme inhibitor affected significantly the maximum concentration (95% CI on the difference 14%, 124% for itraconazole and -23%, 40% for fluconazole) or elimination half-life (95% CI on the difference -42%, 120% for itraconazole and -24%, 61% for fluconazole) of 3-keto-desogestrel.


CONCLUSIONS
According to the present study, the biotransformation of desogestrel to 3-keto-desogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier. However, the further metabolism of 3-keto-desogestrel seems to be catalyzed by CYP3A4.
Korhonen
Tuomas
T
Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku University Hospital, Turku, Finland. tukorho@utu.fi
Tolonen
Ari
A
Uusitalo
Jouko
J
Lundgren
Stefan
S
Jalonen
Jorma
J
Laine
Kari
K
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D003280:Contraceptives, Oral, Synthetic / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D017135:Desogestrel / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology*
D003280:Contraceptives, Oral, Synthetic; C400322:cytochrome P-450 CYP2C subfamily; C044815:etonogestrel; D017135:Desogestrel; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating