Blane G F, Pinaroli F
Nouv Presse Med. 1980 Dec 22;9(49):3737-46.
Chronic toxicity studies of fenofibrate were carried out in rats (3 months), dogs (7 et 24 months) and Rhesus monkeys (12 months). The results in the last named species (78 animals) were of particular interest, since the treated monkeys had normal size liver without histological abnormalities. Electron microscopy showed no increase in the number of hepatic peroxisomes. Long-term toxicity studies in rats failed to show any increase in the incidence of altered hepatocytes or of neoplastic tumours in treated animals. However, a few peroxisomes were found in animals receiving the highest doses of fenofibrate. In reproduction studies there was no evidence of teratogenic effects in rats with doses 45 times higher than the human dose, nor in rabbits with doses of 300 mg/kg/day. In mutagenicity studies fenofibrate proved unable to bind with DNA and could not, therefore, have any effect on genes. The side-effects encountered in clinical practice (e.g. digestive disorders, sexual fatigue, myalgia, alopecia) were rare and obliged to discontinue treatment in very few cases. Long-term clinical trials failed to demonstrate any fenofibrate-induced pathology, such as malignant or benign tumours, or biliary or urinary lithiasis. Serum transaminases were increased in 10 to 20% of the patients, but the rise was transient and never reached pathological levels. Electron microscope study of liver biopsies from patients treated with fenofibrate showed no proliferation of peroxisomes.
非诺贝特的慢性毒性研究在大鼠（3个月）、狗（7个月和24个月）和恒河猴（12个月）身上进行。对最后提到的物种（78只动物）的研究结果尤其令人关注，因为接受治疗的猴子肝脏大小正常，没有组织学异常。电子显微镜检查显示肝过氧化物酶体数量没有增加。在大鼠身上进行的长期毒性研究未能显示接受治疗的动物中肝细胞改变或肿瘤发生率有任何增加。然而，在接受最高剂量非诺贝特的动物中发现了一些过氧化物酶体。在生殖研究中，没有证据表明在剂量比人类剂量高45倍的大鼠中或在剂量为300毫克/千克/天的兔子中有致畸作用。在致突变性研究中，非诺贝特被证明无法与DNA结合，因此对基因没有任何影响。临床实践中遇到的副作用（如消化系统紊乱、性疲劳、肌痛、脱发）很少见，在极少数情况下才需要停药。长期临床试验未能证明非诺贝特会引发任何病理学变化，如恶性或良性肿瘤，或胆石症或尿路结石。10%至20%的患者血清转氨酶升高，但升高是短暂的，从未达到病理水平。对接受非诺贝特治疗的患者进行肝脏活检的电子显微镜研究显示过氧化物酶体没有增殖。
