Work

Retinoic Acid Is Not Involved in Fluconazole-Induced Alopecia: Evaluation in a Human Cohort and Rat Model

Year: 2016

Type: article

Abstract: Background. The association of alopecia with fluconazole was first noted by Pappas et al, and it was speculated by others these effects were possibly related to an unidentified P450 interaction between fluconazole and retinoic acid derivatives given the “retinoid-like” toxicity profile of hair loss, dry skin and mucus membranes, and nail changes observed in some patients on fluconazole. We sought to evaluate the hair-cycle specific changes of fluconazole in a rat model and to determine if any association with retinoic acid levels was noted in the model or a clinical cohort. Methods. Male Wistar rats weighing 200–220 gm (Charles River Laboratories) were fed a standard diet. Rats were randomized 1:1 to fluconazole (35 mg/kg/day) or no fluconazole and sacrificed on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, and 70. Fifty hair samples from the caudal and 50 from the cranial aspect were obtained for microscopic examination at each time point. Plasma, skin, liver, and brain samples were obtained at each time point for microscopic examination and retinoic acid quantification by HPLC (UC-Berkley Napoli Lab). Plucked and intact hair tissue samples were staged in blinded fashion by UC-Davis veterinary dermatopathology. Human patients complaining of alopecia while on fluconazole also underwent plasma retinoic acid determination and hair growth assessment. Results. Fluconazole precipitated follicles into a state of premature rest (telogen effluvium) compared to the untreated group by day 21 in a rat model. Despite the inhibition of CYP26A1 by fluconazole administration, plasma and tissue levels of retinoic acid were no different between groups in either rats or human patients. Conclusion. Fluconazole promotes the development of telogen effluvium and although retinoic acid levels were not elevated in the plasma or tissues of either the rat model or human patients, subcellular effects cannot be ruled out. Future work examining the mechanism of fluconazole-induced alopecia (direct or indirect mechanisms) should be undertaken. Disclosures. G. R. Thompson, Astellas: Consultant, Consulting fee and Grant recipient

Source: Open Forum Infectious Diseases

DOI: 10.1093/ofid/ofw172.1323