Lanthanum carbonate is considered to be the most potent of a new generation of noncalcium phosphate binders used to treat hyperphosphataemia in chronic kidney disease (CKD), a condition associated with progressive bone and cardiovascular pathology and a markedly elevated risk of death. Its phosphate-binding action involves ionic binding and precipitation of insoluble complexes within the lumen of the intestine, thereby preventing absorption of dietary phosphate. While pharmacokinetics have little relevance to the efficacy of lanthanum carbonate, they are of fundamental importance when it comes to evaluating safety. When administered as lanthanum carbonate, the oral bioavailability of lanthanum is low (approximately 0.001%). The small absorbed fraction is excreted predominantly in bile, with less than 2% being eliminated by the kidneys. Predictably, therefore, plasma exposure and pharmacokinetics have been shown to be similar in healthy human volunteers and CKD stage 5 patients. With almost complete plasma protein binding, free lanthanum concentrations in patients at steady state are <3 pg/mL. These properties greatly reduce systemic exposure, tissue deposition and the potential for adverse effects. While lanthanum has a variety of calcium-like actions in vitro, there is little or no evidence that these occur in vivo. This paradox is explained by the very low concentrations of circulating free lanthanum ions, which are many orders of magnitude lower than reported effect concentrations in vitro. Safety pharmacology and toxicology evaluations have failed to reveal any significant calcium-like actions in vivo, despite inclusion of high intravenous doses in some cases.Lanthanum carbonate has a low propensity to cause systemic drug interactions due to its poor absorption. However, the higher concentrations present in the gastrointestinal tract can form chelates with some drugs, such as fluoroquinolones, and reduce their absorption. The improved understanding of the pharmacokinetics of lanthanum that has emerged in recent years has helped to explain why the myriad of calcium-like effects described in vitro for lanthanum have little if any relevance in vivo. The pharmacokinetic investigations of lanthanum carbonate formed an important part of the stringent premarketing safety assessment process and have been influential in reassuring both regulators and physicians that the agent can be used safely and effectively in this vulnerable dialysis population.

中文翻译：

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磷酸盐结合剂碳酸镧的临床药代动力学。

碳酸镧被认为是用于治疗慢性肾病 (CKD) 高磷血症的新一代非磷酸钙结合剂中最有效的，慢性肾病 (CKD) 是一种与进行性骨骼和心血管病理学相关的疾病，死亡风险显着升高。其磷酸盐结合作用涉及离子结合和肠腔内不溶性复合物的沉淀，从而阻止膳食磷酸盐的吸收。虽然药代动力学与碳酸镧的功效几乎没有关系，但在评估安全性方面却至关重要。当以碳酸镧形式给药时，镧的口服生物利用度低（约 0.001%）。吸收的小部分主要在胆汁中排泄，少于 2% 被肾脏清除。可以预见，因此，健康人类志愿者和 CKD 5 期患者的血浆暴露和药代动力学已被证明是相似的。由于血浆蛋白几乎完全结合，稳态患者的游离镧浓度 <3 pg/mL。这些特性大大减少了全身暴露、组织沉积和潜在的不利影响。虽然镧在体外具有多种钙样作用，但很少或没有证据表明这些作用在体内发生。这个悖论是由循环游离镧离子的浓度非常低来解释的，它比体外报道的效应浓度低许多数量级。尽管在某些情况下包括高静脉内剂量，但安全药理学和毒理学评估未能揭示任何显着的体内钙样作用。碳酸镧由于其吸收不良而引起全身药物相互作用的倾向较低。然而，胃肠道中存在的较高浓度可与某些药物（如氟喹诺酮类）形成螯合物，并降低其吸收。近年来出现的对镧药代动力学的更好理解有助于解释为什么在体外描述的镧的无数钙样作用在体内几乎没有相关性。碳酸镧的药代动力学研究构成了严格的上市前安全性评估过程的重要组成部分，并且在让监管机构和医生确信该试剂可以安全有效地用于这一易受伤害的透析人群中具有重要影响。