Corcoran G B, Salazar D E, Chan H H
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Toxicol Appl Pharmacol. 1989 Mar 15;98(1):12-24. doi: 10.1016/0041-008x(89)90129-4.
Effects of the diuretic drug furosemide were examined in obese animals to evaluate the hypothesis that organ damage by reactive drug metabolites may be potentiated by this disease. Obese overfed Sprague-Dawley rats that were treated ip with 450 mg/kg furosemide on the basis of total body mass suffered a 58% mortality rate over 24 h. This contrasted with 0% mortality in animals of normal body mass. On the basis of median histopathology scores, organ necrosis was judged to be greater in the liver (2+) and kidneys (1+) of obese rats than in the liver (1+) and kidneys (less than 1+) of normal controls (p less than 0.05). Obese animals demonstrated a fourfold rise in fat mass over controls. The low solubility of furosemide in lipid makes it probable that aggravated drug toxicity in obese rats dosed to total body mass resulted in part from elevated furosemide concentrations in lean body mass. In a subsequent study designed to minimize this possibility, furosemide was administered on the basis of fat-free body mass to equalize initial drug exposure in obese and control rats. Even with this downward dosage adjustment, obese animals suffered increased hepatic necrosis (median score of 2+ versus 0 in treated controls), greater impairment of renal function (plasma creatinine concentration of 2.41 mg/dl versus 0.96 mg/dl in treated controls), and more extensive enzymuria (enzyme excretion 175-300% more elevated than in treated controls). In conclusion, obese rats appear to be at increased risk of furosemide-induced liver and kidney injury due to at least two factors: (1) increased exposure of target organs in lean body mass to furosemide when the dosing of this poorly lipophilic drug was based on total body mass, and (2) increased susceptibility of target organs in lean body mass to furosemide injury when dosing was adjusted downward to reflect fat-free body mass and to equalize initial drug exposure.
在肥胖动物中研究了利尿药呋塞米的作用，以评估这一假说：反应性药物代谢产物造成的器官损害可能会因这种疾病而加剧。根据总体重经腹腔注射450mg/kg呋塞米治疗的过度喂养的肥胖Sprague-Dawley大鼠在24小时内死亡率达58%。这与正常体重动物0%的死亡率形成对比。根据中位组织病理学评分，肥胖大鼠肝脏（2+）和肾脏（1+）的器官坏死程度被判定高于正常对照组的肝脏（1+）和肾脏（小于1+）（p<0.05）。肥胖动物的脂肪量比对照组增加了四倍。呋塞米在脂质中的低溶解度使得按总体重给药的肥胖大鼠药物毒性加重可能部分是由于瘦体重中呋塞米浓度升高所致。在随后一项旨在尽量减少这种可能性的研究中，根据去脂体重给予呋塞米，以使肥胖大鼠和对照大鼠的初始药物暴露量相等。即使进行了这种向下的剂量调整，肥胖动物仍出现肝坏死增加（治疗对照组的中位评分为2+，而对照为0）、肾功能损害更严重（治疗对照组血浆肌酐浓度为0.96mg/dl，而肥胖动物为2.41mg/dl）以及酶尿更广泛（酶排泄比治疗对照组升高175 - 300%）。总之，肥胖大鼠似乎因至少两个因素而面临呋塞米诱导的肝和肾损伤风险增加：（1）当这种亲脂性差的药物按总体重给药时，瘦体重中的靶器官对呋塞米的暴露增加；（2）当剂量向下调整以反映去脂体重并使初始药物暴露量相等时，瘦体重中的靶器官对呋塞米损伤的易感性增加。
