The Open Drug Metabolism Journal
2007, 1 : 7-13Published online 2007 December 18. DOI: 10.2174/1874073100701010007
Publisher ID: TODMJ-1-7
RESEARCH ARTICLE
Itraconazole Bioequivalence Revisited: Influence of Gender on Highly Variable Drugs
* Head of the Pharmaceutical Sciences Department, Faculty of Chemistry, P.O. Box 1157, 11800 Montevideo, Uruguay; Tel: (5982) 4872129; Fax: (5982) 4876677, (5982) 9241906; E-mail: pfagioli@fq.edu.uy
ABSTRACT
Highly variable drugs have been defined as drugs with a residual variability of more than 30% in terms of the ANOVA coefficient of variation. Different approaches have been proposed during the last years to deal with this problem but the topic remains controversial. Itraconazole, a highly variable drug, has low bioavailability with a high CYP3A4 presystemic biotransformation. Also, it has a very poor aqueous solubility which is very dependent on the pH of the dissolution medium. The pregnane X receptor (PXR) has been shown to mediate the genomic effects of progesterone and estradiol in the expression of the cytochrome P-450 gene family, which plays an important role in the metabolism of hormones and xenobiotics. During the menstrual cycle both hormone concentrations vary, providing a rationale for the more variable CYP3A4 activity in women. The analysis of the data of an itraconazole bioequivalence study involving 24 healthy volunteers (12 men and 12 women) carried out by other investigators enables us to conclude that women have less oral bioavailability and more variable AUC than men. Low bioavailability seems to be related with the higher stomach pH observed in women and variability with the aforementioned menstrual cycle incidence on both pH and CYP3A4 expression. The lower variability observed in men made it possible to discriminate differences in AUC’s variability displayed by each brand.