Hummler H, Richter W F, Hendrickx A G
F. Hoffmann-LaRoche Ltd, Basel, Switzerland.
Toxicol Appl Pharmacol. 1993 Sep;122(1):34-45. doi: 10.1006/taap.1993.1169.
The potential developmental toxicity of fleroxacin was studied (Phase I) and its pharmacokinetics was compared to ciprofloxacin, temafloxacin, and norfloxacin (Phase II) in the cynomolgus macaque (Macaca fascicularis). Phase I studies involved oral administration of fleroxacin (35 and 70 mg/kg-day) during Gestational Days (GD) 20-34 or 35-49 (N = 10/group); controls received vehicle only. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality (4/10, 40%; GD 20-34) were observed at 70 mg/kg-day. Urinary excretion of estrogen conjugates was reduced for females with nonviable pregnancies during both treatment periods (GD 20-34 and 35-49), although steroid hormone levels in serum remained unchanged during treatment; no malformations or growth retardation were observed at gross examination. For Phase II studies, the pharmacokinetics of fleroxacin (70 mg/kg), ciprofloxacin (100 mg/kg), temafloxacin (100 mg/kg), and norfloxacin (150 mg/kg) were studied during a 3-day oral treatment regimen in the nonpregnant (N = 12; 3/quinolone) and pregnant (N = 3; fleroxacin only) macaque. Serial blood samples were collected on the first and third days of treatment in all animals; for pregnant females, the conceptus was removed on GD 31 for analysis of fleroxacin levels. Marked differences between the quinolones were noted in the AUC0-24 hr for nonpregnant females. Based on AUC0-24 hr on the first day of treatment, the rank order was fleroxacin > temafloxacin > ciprofloxacin > norfloxacin. On the third of treatment, the rank order for exposure was temafloxacin > fleroxacin > ciprofloxacin > norfloxacin. Overall, results indicated (1) no marked differences in pharmacokinetic parameters in pregnant versus nonpregnant females, (2) fleroxacin levels in embryonic tissues were similar to maternal plasma levels, and (3) there was a correlation between exposure and embryolethal doses for all fluoroquinolones which resulted in embryolethality except norfloxacin.
在食蟹猴（猕猴）中研究了氟罗沙星的潜在发育毒性（I期），并将其药代动力学与环丙沙星、替马沙星和诺氟沙星进行了比较（II期）。I期研究包括在妊娠第20 - 34天或35 - 49天口服氟罗沙星（35和70 mg/kg·天）（每组N = 10）；对照组仅接受赋形剂。在70 mg/kg·天剂量下观察到母体毒性增加（体重减轻、厌食、呕吐）和胚胎致死率（4/10，40%；妊娠第20 - 34天）。在两个治疗期（妊娠第20 - 34天和35 - 49天），非存活妊娠雌性的雌激素结合物尿排泄减少，尽管治疗期间血清中的类固醇激素水平保持不变；大体检查未观察到畸形或生长迟缓。对于II期研究，在非妊娠（N = 12；每种喹诺酮3只）和妊娠（N = 3；仅氟罗沙星）的猕猴中，在3天口服治疗方案期间研究了氟罗沙星（70 mg/kg）、环丙沙星（100 mg/kg）、替马沙星（100 mg/kg）和诺氟沙星（150 mg/kg）的药代动力学。在所有动物治疗的第一天和第三天采集系列血样；对于妊娠雌性，在妊娠第31天取出胚胎用于分析氟罗沙星水平。在非妊娠雌性的AUC0 - 24小时中，喹诺酮类药物之间存在显著差异。基于治疗第一天的AUC0 - 24小时，排序为氟罗沙星>替马沙星>环丙沙星>诺氟沙星。在治疗第三天，暴露的排序为替马沙星>氟罗沙星>环丙沙星>诺氟沙星。总体而言，结果表明：（1）妊娠和非妊娠雌性的药代动力学参数无显著差异；（2）胚胎组织中的氟罗沙星水平与母体血浆水平相似；（3）除诺氟沙星外，所有导致胚胎致死的氟喹诺酮类药物的暴露量与胚胎致死剂量之间存在相关性。
