ice treated for 2years with the 2highest doses of 45 and 158mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas.
The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin-induced hyperprolactinemia. It is not known if tamsulosin elevates prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.
Mutagenesis:
Dutasteride: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test.
Tamsulosin: Tamsulosin produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in CHO cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay.
Impairment of Fertility:
Dutasteride: Treatment of sexually mature male rats with dutasteride at 0.1- to 110-fold the MRHD (animal doses of 0.05, 10, 50, and 500mg/kg/day for up to 31weeks) resulted in dose- and time-dependent decreases in fertility; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes in the male reproductive organs. The fertility effects were reversed by recovery week 6 at all doses, and sperm counts were normal at the end of a 14-week recovery period. The 5 alpha-reductase–related changes consisted of cytoplasmic vacuolation of tubular epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles. The microscopic changes were no longer present at recovery week 14 in the low-dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17ng/mL) were detected in the serum of untreated female rats mated to males dosed at 10, 50, or 500mg/kg/day for 29 to 30weeks.
In a fertility study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30mg/kg/day resulted in reduced litter size, increased embryo resorption and feminization of male fetuses (decreased anogenital distance) at 2- to 10-fold the MRHD (animal doses of 2.5mg/kg/day or greater). Fetal body weights were also reduced at less than 0.02-fold the MRHD in rats (0.5mg/kg/day).
Tamsulosin: Studies in rats revealed significantly reduced fertility in males at approximately 50times the MRHD based on AUC (single or multiple daily doses of 300mg/kg/day of tamsulosin hydrochloride). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible showing improvement by 3days after a single dose and 4weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 0.2 and 16times the MRH |
