Hendrickx A G, Tzimas G, Korte R, Hummler H
California Regional Primate Research Center, University of California, Davis 95616, USA.
J Med Primatol. 1998 Dec;27(6):310-8. doi: 10.1111/j.1600-0684.1998.tb00081.x.
To further define teratogenicity associated with 13-cis-retinoic acid (13-cis-RA) in the cynomolgus monkey, the drug was orally administered on three different treatment regimens. Experiment (Exp.) 1 (2.5 mg/kg/day, gestational day [GD] 12-27, n = 11) investigated the teratogenicity of a single daily dose of 13-cis-RA administered shortly after embryo implantation. Pharmacokinetic sampling was done to determine retinoid profiles on the first (GD12) and last (GD27) days of treatment. Exposure to 13-cis-RA during early organogenesis in Exp. 2 (2.5 mg/kg/day, GD20-27, and 2 x 2.5 mg/kg/day, GD28-30, n = 5) investigated the potential adverse effects of 13-cis-RA on the developing limb. The use of multiple doses of 13-cis-RA in Exp. 3 (2 x 2.5 mg/kg/day, GD26-27, n = 5) investigated the necessity of double dosing on the induction of retinoid embryopathy in the macaque. Malformations of retinoid target organs as well as embryolethality were most prevalent when single daily doses of 13-cis-RA were administered during pre- and early organogenesis in Exp. 1. Moreover, multiple doses on GD26-27 failed to induce any manifestation of abnormal development in Exp. 3. These results confirm that the lowest observed adverse effect level (LOAEL) in macaques is 2.5 rather than 5.0 times greater than that observed in human pregnancies. Exposure during forelimb development (GD20-30) in Exp. 2 was unsuccessful in inducing defects of this skeletal region, although defects in several retinoid target organs (i.e., cerebellum and internal ear) were present, indicating that a teratogenic threshold was achieved. Pharmacokinetic analysis of 13-cis-RA and its metabolites on GD12 and 27 in Exp. 1 showed considerable exposure to the administered drug and its 4-oxo-metabolite. In contrast, the exposure to all-trans-RA was negligible. The results support the use of a specific treatment schedule in early gestation in the macaque as the most appropriate model for characterizing the teratogenic potential of retinoids in humans.
为进一步明确食蟹猴中与13 - 顺式视黄酸（13 - cis - RA）相关的致畸性，该药物采用三种不同治疗方案进行口服给药。实验（Exp.）1（2.5毫克/千克/天，妊娠第[GD]12 - 27天，n = 11）研究了胚胎着床后不久每日单次给予13 - cis - RA的致畸性。在治疗的第一天（GD12）和最后一天（GD27）进行药代动力学采样以确定类视黄醇谱。实验2（2.5毫克/千克/天，GD20 - 27，以及2×2.5毫克/千克/天，GD28 - 30，n = 5）中，在早期器官形成期暴露于13 - cis - RA，研究了13 - cis - RA对发育中肢体的潜在不良影响。实验3（2×2.5毫克/千克/天，GD26 - 27，n = 5）中使用多剂量的13 - cis - RA，研究了猕猴中双剂量给药对诱导类视黄醇胚胎病的必要性。在实验1中，当在器官形成前期和早期每日单次给予13 - cis - RA时，类视黄醇靶器官的畸形以及胚胎致死率最为普遍。此外，在实验3中，GD26 - 27给予多剂量未能诱导任何异常发育表现。这些结果证实，食蟹猴中观察到的最低不良效应水平（LOAEL）为2.5，而非人类妊娠中观察到的5.0倍。尽管存在几个类视黄醇靶器官（即小脑和内耳）的缺陷，但实验2中在前肢发育期间（GD20 - 30）暴露未能诱导该骨骼区域的缺陷，这表明达到了致畸阈值。实验1中对GD12和27时13 - cis - RA及其代谢物的药代动力学分析显示，给药药物及其4 - 氧代代谢物有相当程度的暴露。相比之下，全反式视黄酸（all - trans - RA）的暴露可忽略不计。这些结果支持在食蟹猴妊娠早期采用特定治疗方案，作为表征类视黄醇对人类致畸潜力的最合适模型。
