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首页> 外文期刊>European journal of pharmaceutical sciences >The pharmacokinetics of pulmonary insulin in the in vitro isolated perfused rat lung: implications of metabolism and regional deposition.
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The pharmacokinetics of pulmonary insulin in the in vitro isolated perfused rat lung: implications of metabolism and regional deposition.

机译：体外离体灌流大鼠肺中肺胰岛素的药代动力学：代谢和区域沉积的影响。

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The pharmacokinetics of several lung disposition pathways for pulmonary insulin were studied and modeled in the isolated perfused rat lung (IPRL). Insulin solution was administered by forced instillation into the airways of the IPRL as 0.1 or 0.02 ml doses of coarse spray, with or without bacitracin (BAC), N-ethylmaleimide (NEM) and atrial natriuretic peptide (ANP). Each insulin absorption profile was fitted to a kinetic model that incorporated the distribution fraction of the dose reaching the lobar region (DF) and the rate constants for absorption into perfusate (k(a)) and non-absorptive loss (k(nal)); k(nal) was shown to be due to the sum of mucociliary clearance and metabolism. Insulin absorption occurred largely by passive diffusion with values for k(a) = 0.39-0.50 h(-1). With DF = 0.91 following 0.1 ml doses, 11.9 +/- 3.4% of bioavailabilities were observed in 1h. In contrast, derived values for k(nal) = 2.34-3.45 h(-1) were significantly larger than the rate constant for mucociliary clearance determined previously in this IPRL (0.96-1.74 h(-1)) due to lung metabolism. Indeed, BAC, but neither NEM nor ANP, was found to decrease the value of k(nal), which suggested that BAC-inhibitable lung ectopeptidases, and not insulin degrading enzyme (IDE), were responsible for this pulmonary metabolism. Shallower lung distribution with DF = 0.73 following 0.02 ml doses resulted in reduced values for k(a) = 0.27 h(-1) and k(nal) = 2.79 h(-1), indicating that these kinetic processes may be lung-region dependent, even within this model and emphasizing the likely importance of reliable lung deposition in vivo.
机译：在分离的灌注大鼠肺（IPRL）中研究了肺部胰岛素的几种肺部处置途径的药代动力学并对其进行了建模。通过将0.1或0.02毫升剂量的粗喷雾剂强制滴入IPRL的气道中，使用或不使用杆菌肽（BAC），N-乙基马来酰亚胺（NEM）和心钠素（ANP）来给予胰岛素溶液。每个胰岛素吸收曲线都适合一个动力学模型，该模型结合了到达肺叶区域（DF）的剂量分布分数以及吸收到灌注液（k（a））和非吸收损失（k（nal））的速率常数。 ; k（nal）被证明是由于粘膜纤毛清除和代谢的总和。胰岛素吸收主要通过被动扩散发生，其k（a）= 0.39-0.50 h（-1）。 0.1 ml剂量后DF = 0.91，在1小时内观察到11.9 +/- 3.4％的生物利用度。相反，k（nal）= 2.34-3.45 h（-1）的派生值显着大于先前在此IPRL中确定的粘膜纤毛清除率常数（0.96-1.74 h（-1）），这是由于肺代谢所致。实际上，发现BAC降低了k（nal）的值，但NEM和ANP都没有降低k（nal）的值，这表明BAC抑制性肺表肽酶而不是胰岛素降解酶（IDE）引起了这种肺代谢。 0.02 ml剂量后DF = 0.73的较浅的肺分布导致k（a）= 0.27 h（-1）和k（nal）= 2.79 h（-1）的值减小，表明这些动力学过程可能在肺区域甚至在该模型中也是如此，并强调了体内可靠的肺部沉积的可能重要性。

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