Shiffman M L, Keith F B, Moore E W
Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Gastroenterology. 1990 Dec;99(6):1772-8. doi: 10.1016/0016-5085(90)90486-k.
Ceftriaxone, a semisynthetic third-generation cephalosporin, has recently been associated with biliary sludge formation. Analysis of the biliary concretions induced by this agent shows a calcium salt of ceftriaxone. The present in vitro studies were undertaken to provide insight into the pathogenesis of ceftriaxone-associated biliary sludge formation by evaluating possible interactions that may exist between calcium, bile salts, and ceftriaxone. Ceftriaxone possessed high calcium-binding affinity. The formation constant for the calcium ceftriaxone salt at 37 degrees C was about 157.3 L/mol; stoichiometry of the salt was 1:1, i.e., calcium ceftriaxone. The calcium-binding property of ceftriaxone was observed to be additive to that of taurocholate in mixed taurocholate-ceftriaxone solutions. Although the solubility product constant for calcium ceftriaxone was only 1.62 x 10(-6) mol/L2, marked metastability was observed; neither visible nor microscopic precipitates developed until the [Ca2+] x [ceftriaxone] ion product exceeded the solubility product constant by a factor of 10.4. Metastability of the calcium ceftriaxone salt was also observed in human gallbladder bile in vitro. Estimates of human biliary calcium ceftriaxone solubility in vivo were than calculated from previously-reported values for biliary [Ca2+], [ceftriaxone], and from the solubility product constant as defined in this study. Calculated saturation indices for calcium-ceftriaxone in human bile generally increased (corresponding to a decrease in solubility) with increasing ceftriaxone dose. At doses less than or equal to 1 g, saturation index was well within the metastable range of this calcium-salt. However, at doses greater than or equal to 2 g, the saturation index surpassed the metastable limit. Under these conditions, precipitation of ceftriaxone could occur. It was concluded that the development of ceftriaxone-induced biliary sludge is a solubility problem that occurs in patients receiving high-dose treatment (greater than or equal to 2 g). This study proposes that the risk of developing ceftriaxone-associated biliary "pseudolithiasis" increases with increasing ceftriaxone dose and in patients with impaired gallbladder emptying.
头孢曲松是一种半合成的第三代头孢菌素，最近被发现与胆泥形成有关。对由该药物引起的胆石的分析显示为头孢曲松钙盐。进行目前的体外研究是为了通过评估钙、胆盐和头孢曲松之间可能存在的相互作用，深入了解头孢曲松相关胆泥形成的发病机制。头孢曲松具有高钙结合亲和力。头孢曲松钙盐在37℃时的形成常数约为157.3 L/mol；盐的化学计量比为1:1，即头孢曲松钙。在混合牛磺胆酸盐-头孢曲松溶液中，观察到头孢曲松的钙结合特性与牛磺胆酸盐的特性具有加和性。尽管头孢曲松钙的溶度积常数仅为1.62×10⁻⁶ mol/L²，但观察到明显的亚稳性；直到[Ca²⁺]×[头孢曲松]离子积超过溶度积常数10.4倍时，才出现可见或微观沉淀。在体外人胆囊胆汁中也观察到头孢曲松钙盐的亚稳性。根据先前报道的胆汁中[Ca²⁺]、[头孢曲松]值以及本研究中定义的溶度积常数，计算了人体内头孢曲松钙的溶解度估计值。随着头孢曲松剂量的增加，人胆汁中头孢曲松钙的计算饱和指数通常会增加（对应于溶解度降低）。在剂量小于或等于1 g时，饱和指数完全处于该钙盐的亚稳范围内。然而，在剂量大于或等于2 g时，饱和指数超过了亚稳极限。在这些条件下，头孢曲松可能会沉淀。得出的结论是，头孢曲松诱导的胆泥形成是一个溶解度问题，发生在接受高剂量治疗（大于或等于2 g）的患者中。本研究提出，头孢曲松相关胆“假结石症”的发生风险随着头孢曲松剂量的增加以及胆囊排空受损的患者而增加。
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