Cross David M, Horsley Elizabeth, Derzi Mazin, Owen Keith, Stavros Fiona L
Pfizer Ltd., Sandwich, Kent, UK.
Birth Defects Res B Dev Reprod Toxicol. 2012 Oct;95(5):327-36. doi: 10.1002/bdrb.21021. Epub 2012 Aug 13.
Sitaxentan sodium (Thelin) is a once daily, orally bioavailable, highly selective endothelin A receptor antagonist. Initially approved for the treatment of pulmonary arterial hypertension, sitaxentan was withdrawn in 2010 following the recognition of a pattern of idiosyncratic liver injury. During development of this drug, a series of nonclinical studies investigated the effects of orally administered sitaxentan on fertility, embryofetal development, and pre- and postnatal development in the rat; results of these studies are reported here. In the fertility study, sitaxentan did not affect mating behavior, fertility, sperm morphology, or estrous cycle. Sitaxentan was teratogenic in the embyrofetal development study, which was expected based on its pharmacologic mechanism of action. Teratogenic effects included malformations of the head, mouth, face, and large blood vessels. In the pre- and postnatal study, sitaxentan administration was associated with reduced pup survival, large or abnormally shaped livers, and delays in markers of auditory and sexual development. Sitaxentan was detected in plasma of suckling pups receiving milk from females dosed with sitaxentan. These nonclinical study findings were reflected in the sitaxentan product label warnings.
昔多芬坦钠（Thelin）是一种每日服用一次、口服生物利用度高、高度选择性的内皮素A受体拮抗剂。昔多芬坦最初被批准用于治疗肺动脉高压，在发现一种特异质性肝损伤模式后于2010年撤市。在该药物的研发过程中，一系列非临床研究调查了口服昔多芬坦对大鼠生育力、胚胎-胎儿发育以及出生前和出生后发育的影响；这些研究结果在此报告。在生育力研究中，昔多芬坦不影响交配行为、生育力、精子形态或发情周期。昔多芬坦在胚胎-胎儿发育研究中具有致畸性，基于其药理作用机制这是意料之中的。致畸作用包括头部、口腔、面部和大血管畸形。在出生前和出生后研究中，给予昔多芬坦与幼崽存活率降低、肝脏肿大或形状异常以及听觉和性发育标志物延迟有关。在接受来自服用昔多芬坦的雌性大鼠乳汁的哺乳期幼崽血浆中检测到了昔多芬坦。这些非临床研究结果反映在昔多芬坦产品标签警告中。
