Four weeks of oral isotretinoin treatment causes few signs of general toxicity in male and female Sprague-Dawley rats.
Despite widespread use of isotretinoin for its anti-acne effects and its current evaluation in clinical trials as a cancer treatment, little is known about its general toxicity in adult nonpregnant animals, particularly after oral administration which mimics the human route. Here, adult male and female Sprague-Dawley rats were gavaged daily with 0 (soy oil), 7.5, or 15 mg/kg isotretinoin for 28 days during which time body weight, food/water intake, and estrous phase were measured. At sacrifice, organ weights were collected and concentrations of dopamine (DA), serotonin and metabolites were measured in frontal cortex, striatum, hippocampus, and diencephalon. Food intake was mildly decreased in both treated groups (approximately 15% in males and 7% in females); however, body weight and water consumption were unaffected. The estrous cycle appeared slightly affected (i.e., lengthened by 15 mg/kg, and both treated groups appeared to have less time in diestrus and more time in estrus). Kidney/body weight ratio was decreased by 7.5 and 15 mg/kg isotretinoin and spleen/body weight ratio was increased in the 7.5 mg/kg group. Males of the 7.5 mg/kg group exhibited significantly higher gonad/body weight ratios than did same-sex controls. Concentrations of monoamine and metabolites in the frontal cortex and diencephalon were unaffected. Nor were striatal DA and DOPAC concentrations affected; however, there were isolated effects on striatal HVA and 5-HIAA. Hippocampal DA concentrations were marginally increased. These data indicate mild effects resulting from oral isotretinoin treatment at doses which likely produce serum levels within the range of humans.
Ferguson
Sherry A
SA
Division of Neurotoxicology, HFT-132, National Center for Toxicological Research/FDA, 3900, NCTR Road, Jefferson, AR 72079, USA. sferguson@nctr.fda.gov
Cisneros
F Javier
FJ
Gough
Bobby J
BJ
Ali
Syed F
SF
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003879:Dermatologic Agents / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D015474:Isotretinoin / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013737:Testis / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests
D016588:Anticarcinogenic Agents; D003879:Dermatologic Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D015474:Isotretinoin; D004298:Dopamine