title: In vivo pharmacokinetics and in vitro antifungal activity of iodiconazole, a new triazole, determined by microdialysis sampling.
abstract: In this study, the distribution of a new triazole drug, iodiconazole, in rat dermal interstitial fluid and blood was investigated by double-site microdialysis following dermal administration. It was demonstrated that well-calibrated microdialysis sampling in rats could be used to assess the percutaneous penetration kinetics of iodiconazole cream. Iodiconazole penetrated rapidly and cleared slowly from the dermis. The ratio of area under the concentration-time curve in dermis (AUC(dermis)) to that in blood (AUC(blood)) was close to 20, which meant that the free iodiconazole concentration had a higher distribution in the target tissue. Subsequently, the in vitro antifungal activities of iodiconazole were evaluated and were compared with those of fluconazole, itraconazole, ketoconazole, miconazole and terbinafine. Iodiconazole exhibited broad spectrum and potent activity against 12 kinds of clinically pathogenic fungi. The drug concentration percentage inhibition curves versus time of iodiconazole against the tested fungi elucidated the two-dimensional relationship (concentration-effect) following drug administration, indicating that the percentage inhibition (%) of iodiconazole compared with the drug-free control in dermal dialysate were all >90% in the 900-min sampling time following dermal administration. Moreover, integration of in vivo pharmacokinetic data with the in vitro minimum inhibitory concentration (MIC) provided iodiconazole AUC/MIC ratios in rat dermis and blood of 347.7h and 18.8h, respectively, with an iodiconazole cream (2%) dosage of 0.033 g/cm² (3 cm×5 cm). These findings show a reservoir effect in the skin following topical application. Iodiconazole topical cream may be a future alternative for treatment of dermatophytosis in humans.
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Cao
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.forename: Guorong
authors.initials: G
authors.lastname: Fan
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001596:Benzylamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001774:Blood Chemical Analysis; D005658:Fungi / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000737:chemistry; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: C539632:1-(1H-1,2,4-triazole)-2-(2,4-difluorophenyl)-3-(N-methyl-N-(4-iodobenzyl)amino)-2-propanol; D000935:Antifungal Agents; D001596:Benzylamines; D014230:Triazoles