ELIZA cgi-bash version rev. 1.91
- Medical English LInking keywords finder for the PubMed Zipped Archive (ELIZA) -

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298283 occurrences (No.79 in the rank) during 5 years in the PubMed. [cache]
279) Leveraging data from transfected human embryonic kidney 293 cells and primary human hepatocytes, we further evaluated mechanisms involved in the observed plasma-facilitated uptake transport.
--- ABSTRACT ---
PMID:33139461 DOI:10.1124/dmd.120.000134
2021 Drug metabolism and disposition: the biological fate of chemicals
* Effect of Human Plasma on Hepatic Uptake of Organic Anion-Transporting Polypeptide 1B Substrates: Studies Using Transfected Cells and Primary Human Hepatocytes.
- Current challenges with the in vitro-in vivo extrapolation (IVIVE) of hepatic uptake clearance involving organic anion-transporting polypeptide (OATP) 1B1/1B3 hinder drug design strategies. Here we evaluated the effect of 100% human plasma on the uptake clearance using transfected human embryonic kidney (HEK) 293 cells and primary human hepatocytes and assessed IVIVE. Apparent unbound uptake clearance (PSinf,u) increased significantly (P < 0.05) in the presence of plasma (vs. buffer incubations) for about 50% of compounds in both OATP1B1-transfected and wild-type HEK cells. Thus, plasma showed a minimal effect on the uptake ratios. With cultured human hepatocytes, plasma significantly (P < 0.05) increased PSinf,u for 11 of 19 OATP1B substrates (median change of 2.1-fold). Cell accumulation in HEK cells and hepatocytes was also increased for tolbutamide, which is not an OATP substrate. Plasma-to-buffer ratio of PSinf,u obtained in hepatocytes showed a good correlation with unbound fraction in plasma, and the relationship was best described by a "facilitated-dissociation" model. IVIVE was evaluated for the 19 OATP1B substrates using hepatocyte data in the presence of buffer and plasma. PSinf,u from buffer incubations markedly underpredicted hepatic intrinsic clearance (calculated via well stirred and parallel tube models) with an estimated bias of 0.10-0.13. Predictions improved when using PSinf,u from plasma incubations; however, considerable systemic underprediction was still apparent (0.19-0.26 bias). Plasma data with a global scaling factor of 3.8-5.3 showed good prediction accuracy (95% predictions within 3-fold; average fold error = 1.7, bias = 1). In summary, this study offers insight into the effect of plasma on the uptake clearance and its scope in improving IVIVE. SIGNIFICANCE STATEMENT: Our study using diverse anionic compounds shows that human plasma facilitates organic anion-transporting polypeptide 1B-mediated as well as passive uptake clearance, particularly for the highly bound compounds. Leveraging data from transfected human embryonic kidney 293 cells and primary human hepatocytes, we further evaluated mechanisms involved in the observed plasma-facilitated uptake transport. Enhanced hepatic uptake rate in the presence of plasma could be of relevance, as such mechanisms likely prevail in vivo and emphasize the need to maintain physiologically relevant assay conditions to achieve improved translation of transport data.
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(1)83 research (16)4 validation (31)2 and (46)2 high-quality
(2)43 studies (17)3 confirmed (32)2 attention (47)2 inform
(3)22 investigation (18)3 demonstrate (33)2 characterization (48)2 insight
(4)9 analysis (19)3 demonstrated (34)2 clinical (49)2 reduce
(5)9 study (20)3 highlight (35)2 considerations (50)2 research,
(6)7 the (21)3 identify (36)2 develop (51)2 screening
(7)7 work (22)3 in (37)2 developing (52)2 showed
(8)5 development (23)3 investigated (38)2 discussion (53)2 structure-based
(9)5 evidence (24)3 investigations (39)2 divided (54)2 studied
(10)4 evaluate (25)3 literature (40)2 enhanced (55)2 supported
(11)4 evaluation (26)3 our (41)2 evaluated (56)2 tested
(12)4 exploration (27)3 show (42)2 evaluations (57)2 this
(13)4 explore (28)3 we (43)2 examined (58)2 understand
(14)4 improve (29)2 aid (44)2 explored (59)2 understanding
(15)4 investigate (30)2 analyses (45)2 extend

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--- WordNet output for further --- =>1.さらにずっと, さらに先に, 一層遠く, その上, 更に, もっと遠い, なお一層の, さらに遠く, もっと先に, いっそうはるかに, さらにまた, さらになお(furthermore), 2.進める, 助成する, 促進する Overview of verb further The verb further has 2 senses (first 2 from tagged texts) 1. (7) foster, further -- (promote the growth of; "Foster our children's well-being and education") 2. (2) promote, advance, boost, further, encourage -- (contribute to the progress or growth of; "I am promoting the use of computers in the classroom") Overview of adj further The adj further has 1 sense (first 1 from tagged texts) 1. (2) further, farther -- (more distant in especially degree; "nothing could be further from the truth"; "further from our expectations"; "farther from the truth"; "farther from our expectations") Overview of adv further The adv further has 3 senses (first 3 from tagged texts) 1. (33) further, farther -- (to or at a greater extent or degree or a more advanced stage (`further' is used more often than `farther' in this abstract sense); "further complicated by uncertainty about the future"; "let's not discuss it further"; "nothing could be further from the truth"; "they are further along in their research than we expected"; "the application of the law was extended farther"; "he is going no farther in his studies") 2. (10) further -- (in addition or furthermore; "if we further suppose"; "stated further that he would not cooperate with them"; "they are definitely coming; further, they should be here already") 3. (1) farther, further -- (to or at a greater distance in time or space (`farther' is used more frequently than `further' in this physical sense); "farther north"; "moved farther away"; "farther down the corridor"; "the practice may go back still farther to the Druids"; "went only three miles further"; "further in the future") Overview of adv far The adv far has 5 senses (first 4 from tagged texts) 1. (61) far -- (to a considerable degree; very much; "a far far better thing that I do"; "felt far worse than yesterday"; "eyes far too close together") 2. (39) far -- (at or to or from a great distance in space; "he traveled far"; "strayed far from home"; "sat far away from each other") 3. (22) far -- (at or to a certain point or degree; "I can only go so far before I have to give up"; "how far can we get with this kind of argument?") 4. (3) far -- (remote in time; "if we could see far into the future"; "all that happened far in the past") 5. far -- (to an advanced stage or point; "a young man who will go very far") --- WordNet end ---