No abstract

A simple and robust novel approach for the collection of small plasma volumes from rodent TK studies has been demonstrated.

Nonepithelial malignant tumors of the pancreas are extremely rare neoplasms with a frequency of approximately 0.6%. They are always explored because of a suspected diagnosis of pancreatic carcinoma. Amongst the more than 600 primary pancreatic neoplasms in our pancreatic tumor archive only 5 neoplasms were of nonepithelial origin (one was a malignant peripheral nerve sheath tumor [MPNST], one a leiomyosarcoma, one a malignant mesothelioma, and two were peripheral neuroectodermal tumors [PNET]. The differential diagnosis includes secondary infiltration of the pancreas by mesenchymal tumors of the retroperitoneum, undifferentiated pancreatic carcinoma and, especially in the case of PNET, malignant lymphoma. Preoperative chemotherapy and down-staging can improve the operability and prognosis, especially in PNET.

Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp 2/2 ) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP.