Involvement of the Transporters P-Glycoprotein and Breast Cancer Resistance Protein in Dermal Distribution of the Multikinase Inhibitor Regorafenib and Its Active Metabolites

Regorafenib is a multikinase inhibitor orally administered to colorectal cancer patients, and is known to often exhibit dermal toxicity. The purpose of this study is to clarify possible involvement of P-glycoprotein and breast cancer resistance protein (BCRP) in the dermal accumulation of regorafenib and its active metabolites M-2 and M-5. Following intravenous administration in triple knockout (Abcb1a/1b/bcrp -/-; TKO) and wild-type (WT) mice, delayed plasma clearance of M-2 and M-5, but not regorafenib, was observed in TKO mice compared to WT mice. Elacridar, an inhibitor of both transporters, also caused delayed clearance of M-2 and M-5, suggesting that these transporters are involved in their elimination. Skin-to-plasma concentration ratios of regorafenib, M-2, and M-5 were significantly higher in TKO mice than in WT mice. Elacridar increased skin-to-plasma and epidermis-to-plasma concentration ratios of regorafenib. Basal-to-apical transport of M-2 and M-5 was observed in LLC-PK1-Pgp and MDCKII/BCRP/PDZK1 cells, which was inhibited by elacridar and the BCRP inhibitor Ko143, respectively. The present findings thus indicate that P-glycoprotein and BCRP are involved in the accumulation of regorafenib and its active metabolites in the skin, by affecting either their systemic exposure or their plasma distribution in the circulating blood. © 2017 American Pharmacists Association®.Embargo Period 12 month

Cooking Vessels, Volumes, and Venues: Evidence from LM IIIC Kavousi Vronda and Karphi

Glowacki, K.T., and L.P. Day. “Cooking Vessels, Volumes, and Venues: Evidence from LM IIIC Kavousi Vronda and Karphi.” Abstract of paper read at Διατροφικές συνήθειες και πρακτικές στην Κρήτη διαχρονικά [Dietary Habits and Practices in Crete over Time], Museum of Cretan Ethnology, Voroi, Crete, Greece, September 9–10, 2017.Our understanding of diet and culinary practices at the Late Minoan IIIC settlement sites of Kavousi Vronda and Karphi is based upon several different types of physical evidence that have been recovered through excavation. These include the botanical and faunal remains of plants and animals available to and consumed by the inhabitants; ceramic vessels used for the cooking and consumption of food and drink; built and fixed cooking installations, such as hearths and ovens; and the architectural spaces within the settlements where food preparation and consumption most likely took place. Each type of evidence is, by itself, incomplete and dependent upon differential preservation resulting from site formation processes specific to each archaeological context. Taken together, however, they allow us to gain important insights into key aspects of food cultivation, provisioning, processing, preparation, and convivial practices on Crete in the 12th and 11th centuries BC. In this paper, we will compare and contrast the evidence for food preparation and dining at each site, paying special attention to the forms and sizes of ceramic vessels used for cooking and consumption

Direct inhibition and down-regulation by uremic plasma components of hepatic uptake transporter for sn-38, an active metabolite of irinotecan, in humans

Purpose: Clinical study has previously revealed that plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, was higher in patients with end-stage renal failure than those with normal kidney function although SN-38 is mainly eliminated in the liver. Here, we focused on inhibition by uremic toxins of hepatic SN-38 uptake and down-regulation of uptake transporter(s) by uremic plasma in humans. Methods: We evaluated SN-38 uptake and its inhibition by uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulfate (Indox), hippuric acid (HA) and indole acetate (IA), with cryopreserved human hepatocytes and HEK293 cells stably expressing hepatic uptake transporters, organic anion transporting polypeptides (OATPs). We also collected plasma samples from patients with severe renal failure to examine their effects on mRNA level of OATPs in primary cultured human hepatocytes. Results: SN-38 was taken up by hepatocytes, which showed biphasic saturation patterns. The SN-38 uptake by hepatocytes was significantly inhibited by a uremic toxin mixture including clinically relevant concentrations of CMPF, Indox, HA and IA. Kinetic analyses for OATP-mediated transport revealed that the uptake of SN-38 by OATP1B1 was the highest, followed by OATP1B3. Among the uremic toxins, CMPF exhibited most potent inhibition of OATP1B1-mediated SN-38 uptake and directly inhibited the uptake of SN-38 also in hepatocytes. In addition, gene expression of OATP1B1 and OATP1B3 in hepatocytes was significantly down-regulated by the treatment with the uremic plasma. Conclusions: OATP1B1-mediated hepatic uptake of SN-38 was inhibited by uremic toxins, and gene expression of OATP1B1 was down-regulated by uremic plasma. © 2013 Springer Science+Business Media New York