■对于各种肝脏病变,血浆未结合(UB)和结合(CB)胆红素浓度似乎是偶联的。例如,在酒精性肝硬化中,UB和CB在大范围的总胆红素上大致相同,需要血浆CB最初大量增加(约40倍)才能达到UB水平,然后随着疾病的发展,UB和CB的增加相似。这种耦合要么未被识别,要么被忽略,本文是首次尝试根据已知的肝细胞代谢和膜转运特性对其进行定量解释。
■开发了一种简化的药代动力学模型,并将其应用于各种高胆红素血症病理。该模型的主要特征是基于最近的观察,即大鼠OATP1A和OATP1B肝转运蛋白的双敲除会使血浆CB增加约400倍,表明CB从细胞到血浆的正常快速再循环,并通过OATP再摄取。我们使用OATPCB转运的实验大鼠Km来显示OATP摄取在相对较低的血浆CB浓度下变得饱和,减少吸收,并在某些病理中产生大量(高达1000倍)的CB增加。假设UB和CB竞争OATP转运蛋白,产生在“纯”CB病理中观察到的血浆UB增加。
■该模型准确地描述了纯UB的临床观察到的UB和CB(吉尔伯特,溶血性贫血)和CB(杜宾-约翰逊,转子综合征,胆道闭锁)病理以及肝硬化。
■这个模型是一个初步的,首次尝试定量描述UB和CB药代动力学。希望它将激发更详细的测量和分析。
UNASSIGNED: For a large variety of liver pathologies, the plasma unconjugated (UB) and conjugated (CB) bilirubin concentrations appear to be coupled. For example, in alcoholic cirrhosis, UB and CB are roughly the same over a large range of total bilirubin, requiring an initial massive increase (about 40-fold) in plasma CB to reach the level of UB and then similar increases in UB and CB as the disease progresses. This coupling has been either unrecognized or ignored and this paper is the first attempt to try to explain it quantitatively in terms of known hepatic cell metabolic and membrane transport properties.
UNASSIGNED: A simplified pharmacokinetic model is developed and applied to a variety of hyperbilirubinemic pathologies. A central feature of the model is based on the recent observation that double knockout of the rat OATP1A and OATP1B hepatic transporters produces a roughly 400-fold increase in plasma CB, indicating that there is a normal rapid recycling of CB from the cell to the plasma with reuptake via OATP. We use the experimental rat Km of OATP CB transport to show that OATP uptake becomes saturated at relatively low plasma CB concentrations, decreasing uptake, and producing massive (up to 1000-fold) increases in CB in some pathologies. It is assumed that UB and CB are competing for the OATP transporter, producing the increased plasma UB that is observed in \"pure\" CB pathologies.
UNASSIGNED: The model accurately describes the clinically observed UB and CB for pure UB (Gilbert\'s, hemolytic anemia) and CB (Dubin-Johnson,
Rotor syndrome, biliary atresia) pathologies as well as in cirrhosis.
UNASSIGNED: This model is a preliminary, first attempt to quantitatively describe UB and CB pharmacokinetics. It is hoped that it will stimulate more detailed measurements and analysis.