Bajraktari-Sylejmani Gzona, von Linde Teresa, Burhenne Jürgen, Haefeli Walter Emil, Sauter Max, Weiss Johanna
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Pharmaceutics. 2022 Aug 1;14(8):1610. doi: 10.3390/pharmaceutics14081610.
The human peptide transporter hPepT1 (SLC15A1), physiologically transporting dipeptides and tripeptides generated during food digestion, also plays a role in the uptake of small bioactive peptides and peptide-like drugs. Moreover, it might be addressed in prodrug strategies of poorly absorbed drugs. We hypothesised that the cyclic drug peptides octreotide and pasireotide could be substrates of this transporter because their diameter can resemble the size of dipeptides or tripeptides due to their strong structural curvature and because they reach the systemic circulation in Beagle dogs. For investigating possible hPepT1 substrate characteristics, we generated and characterised a CHO-K1 cell line overexpressing by transfection and selection via magnetic beads. Possible inhibition of the uptake of the prototypical substrate Gly-Sar by octreotide and pasireotide was screened, followed by quantifying the uptake of the cyclic peptides in cells overexpressing compared with the parental cell line. Although inhibition of Gly-Sar uptake was observed, uptake of octreotide and pasireotide was not increased in overexpressing cells, indicating a lack of transport by hPepT1. Our data clearly indicate that octreotide and pasireotide are nonsubstrate inhibitors of hPepT1 and that their oral bioavailability cannot be explained by absorption via hPepT1.
人肽转运体hPepT1（SLC15A1）在生理上负责转运食物消化过程中产生的二肽和三肽，同时在摄取小的生物活性肽和肽类药物方面也发挥作用。此外，在吸收较差药物的前药策略中也可能涉及到它。我们推测环型药物肽奥曲肽和帕瑞肽可能是该转运体的底物，因为它们的直径由于其强烈的结构曲率而类似于二肽或三肽的大小，并且它们在比格犬中能够进入体循环。为了研究hPepT1可能的底物特性，我们通过转染和磁珠筛选生成并鉴定了一种过表达的CHO-K1细胞系。筛选了奥曲肽和帕瑞肽对原型底物甘氨酰-肌氨酸摄取的可能抑制作用，随后与亲本细胞系相比，对过表达细胞中环型肽的摄取进行定量。虽然观察到甘氨酰-肌氨酸摄取受到抑制，但在过表达细胞中奥曲肽和帕瑞肽的摄取并未增加，这表明hPepT1缺乏转运作用。我们的数据清楚地表明，奥曲肽和帕瑞肽是hPepT1的非底物抑制剂，并且它们的口服生物利用度不能用通过hPepT1的吸收来解释。
