In 1959, Ivar Sperber contrasted bile formation with that of urine and proposed that water flow into the canalicular conduit is in response to an osmotic, not a hydrostatic, gradient. Early attempts to support the hypothesis using a bile acid, sodium taurocholate, and the hormone secretin to stimulate bile flow led to conflicting data and a moratorium on attempts to further develop the initial proposal. However, current data amplify the initial proposal and indicate both paracellular and transcellular water flow into hepatic ductules and the canalicular conduit in response to an osmotic gradient. Also, the need to further modify the initial proposal became apparent with the recognition that bile acid aggregates (micelles), which form in the canalicular conduit, generate lecithin-cholesterol vesicles that contain water unrelated to an osmotic gradient. As part of this development is the recent introduction of the fluorescent localization after photobleaching technique for direct determination of hepatic duct flow and clarification of the role of biomarkers such as mannitol and polyethylene glycol 900. With the new paradigm, these biomarkers may prove useful for quantifying paracellular and transcellular water flow, respectively.

1959 年，Ivar Sperber 将胆汁的形成与尿液的形成进行了对比，并提出流入小管的水是对渗透压梯度而不是静水压梯度的响应。早期尝试使用胆汁酸、牛磺胆酸钠和激素促胰液素刺激胆汁流动来支持这一假设，但结果导致数据相互矛盾，并暂停了进一步发展最初提议的尝试。然而，当前的数据放大了最初的提议，并表明细胞旁水和跨细胞水均响应渗透梯度流入肝小管和小管。此外，由于认识到在胆管导管中形成的胆汁酸聚集体（胶束），进一步修改最初提案的必要性变得显而易见。产生卵磷脂-胆固醇囊泡，其中含有与渗透梯度无关的水。作为这一发展的一部分，最近引入了光漂白技术后的荧光定位，用于直接测定肝管流量，并澄清甘露醇和聚乙二醇 900 等生物标志物的作用。通过新的范例，这些生物标志物可能有助于量化分别为细胞旁水流和跨细胞水流。