No abstract

Tamoxifen is widely used to treat oestrogen-dependent carcinoma of the breast. Previous long-term studies have shown that oral administration of tamoxifen induces hepatoproliferative lesions and hepatocellular tumours in rats. 4-hydroxytamoxifen is an active metabolite of tamoxifen undergoing clinical evaluation for the treatment of various non-malignant breast diseases by topical application. In the present study, 4-hydroxytamoxifen was administered daily by cutaneous application for 101 weeks to groups of 50 female Sprague-Dawley rats at 20, 140 or 1000 microg/kg/day. The product was applied with no occlusive bandage and oral ingestion was avoided by application of an Elizabethan collar for 6 h after administration. Treatment with 4-hydroxytamoxifen was clinically well tolerated and induced changes such as decreased food consumption and body weight gain, uterine and ovarian atrophy, mucification of vaginal epithelium and reduced mammary development, all of which were attributed to its pharmacological action. Mortality was significantly lower in the treated animals. The number of animals with palpable masses was similarly reduced. The incidence of mammary tumours and hypophyseal tumours was markedly lower in 4-hydroxytamoxifen-treated animals. The incidence of chronic tubulo-interstitial nephropathies, a common cause of mortality, was also lowered. There was no evidence of a carcinogenic action of 4-hydroxytamoxifen on the liver, genital organs or skin. Plasma levels of 4-hydroxytamoxifen were stable over the duration of the study and were proportional to the administered dose, exceeding clinical plasma levels by 60-fold at the high dose-level. In conclusion, 4-hydroxytamoxifen is not carcinogenic in the rat and reduces the incidence of spontaneous mammary and hypophyseal tumours.

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In order to minimise the occurrence of unexpected toxicities as a new medicine transitions from the preclinical to clinical phases of development, it is vital to understand fundamental similarities and differences between preclinical species and humans. The well-known difference in sensitivity of mice and rats to acetaminophen (APAP) liver injury has been related to differences in the fraction that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). We have used physiologically-based pharmacokinetic modelling to identify doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult. Despite pharmacokinetic and biochemical verification of the equivalent NAPQI insult, serum biomarker and tissue histopathology analyses revealed that mice still exhibited a greater degree of liver injury than rats. Transcriptomic and proteomic analyses highlighted the stronger activation of stress response pathways (including the Nrf2 oxidative stress response and autophagy) in the livers of rats, indicative of a more robust transcriptional adaptation to the equivalent insult. Using RNA-Seq data, we also found that genes associated with these stress responses are expressed at a higher basal level in the livers of rats compared with both mice and humans. Taken together, these data indicate that rats possess a greater basal and adaptive capacity for hepatic stress responses than mice and humans. This has important implications for species selection in preclinical safety testing of drugs associated with reactive metabolite formation and other forms of chemical stress.