Article date: July 2005
By: Tuomas Korhonen, Ari Tolonen, Jouko Uusitalo, Stefan Lundgren, Jorma Jalonen, Kari Laine, in Volume 60, Issue 1, pages 69-75
Aims
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 µg 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.
DOI: 10.1111/j.1365-2125.2005.02382.x
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