ELIZA

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611425 occurrences (No.13 in the rank) during 5 years in the PubMed. [cache]

434) In conclusion, we demonstrate that OATP-mediated hepatic uptake is the major contributor to the clearance of E7766, and inhibition of OATP1B may increase its systemic exposure.

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PMID:33355210 DOI:10.1124/dmd.120.000125

2021 Drug metabolism and disposition: the biological fate of chemicals

* Prediction of Transporter-Mediated Drug-Drug Interactions and Phenotyping of Hepatobiliary Transporters Involved in the Clearance of E7766, a Novel Macrocycle-Bridged Dinucleotide.

- E7766 represents a novel class of macrocycle-bridged dinucleotides and is under clinical development for immuno-oncology. In this report, we identified mechanism of systemic clearance E7766 and investigated the hepatobiliary transporters involved in the disposition of E7766 and potential drug interactions of E7766 as a victim of organic anion-transporting polypeptide (OATP) inhibitors. In bile-duct cannulated rats and dogs, E7766 was mainly excreted unchanged in bile (>80%) and to a lesser extent in urine (<20%). Sandwich-cultured human hepatocytes (SCHHs), transfected cells, and vesicles were used to phenotype the hepatobiliary transporters involved in the clearance of E7766. SCHH data showed temperature-dependent uptake of E7766 followed by active biliary secretion. In vitro transport assays using transfected cells and membrane vesicles confirmed that E7766 was a substrate of OATP1B1, OATP1B3, and multidrug resistance-associated protein 2. Phenotyping studies suggested predominant contribution of OATP1B3 over OATP1B1 in the hepatic uptake of E7766. Studies in OATP1B1/1B3 humanized mice showed that plasma exposure of E7766 increased 4.5-fold when coadministered with Rifampicin. Physiologically based pharmacokinetic models built upon two independent bottom-up approaches predicted elevation of E7766 plasma exposure when administered with Rifampicin, a clinical OATP inhibitor. In conclusion, we demonstrate that OATP-mediated hepatic uptake is the major contributor to the clearance of E7766, and inhibition of OATP1B may increase its systemic exposure. Predominant contribution of OATP1B3 in the hepatic uptake of E7766 was observed, suggesting polymorphisms in OATP1B1 would be unlikely to cause variability in the exposure of E7766. SIGNIFICANCE STATEMENT: Understanding the clearance mechanisms of new chemical entities is critical to predicting human pharmacokinetics and drug interactions. A physiologically based pharmacokinetic model that incorporated parameters from mechanistic in vitro and in vivo experiments was used to predict pharmacokinetics and drug interactions of E7766, a novel dinucleotide drug. The findings highlighted here may shed a light on the pharmacokinetic profile and transporter-mediated drug interaction propensity of other dinucleotide drugs.

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(1)204 in	(7)5 was	(13)3 health	(19)2 range
(2)67 the	(8)4 their	(14)3 on	(20)2 significantly
(3)31 of	(9)4 with	(15)2 null	(21)2 tumor
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--- WordNet output for increase --- =>大きくなる, を増す, 増大させる, 強まる, 増加, 増える, 増やす Overview of noun increase The noun increase has 5 senses (first 5 from tagged texts) 1. (49) addition, increase, gain -- (a quantity that is added; "there was an addition to property taxes this year"; "they recorded the cattle's gain in weight over a period of weeks") 2. (21) increase -- (a change resulting in an increase; "the increase is scheduled for next month") 3. (7) increase, increment, growth -- (a process of becoming larger or longer or more numerous or more important; "the increase in unemployment"; "the growth of population") 4. (3) increase, increment -- (the amount by which something increases; "they proposed an increase of 15 percent in the fare") 5. (3) increase, step-up -- (the act of increasing something; "he gave me an increase in salary") Overview of verb increase The verb increase has 2 senses (first 2 from tagged texts) 1. (86) increase -- (become bigger or greater in amount; "The amount of work increased") 2. (61) increase -- (make bigger or more; "The boss finally increased her salary"; "The university increased the number of students it admitted") --- WordNet end ---