ELIZA

return kwic search for activity out of >500 occurrences
475194 occurrences (No.33 in the rank) during 5 years in the PubMed. [cache]

206) Interestingly, with rifampin, in vivo CYP3A activity was approximately 4-fold higher than in vitro activity.

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PMID:33863817 DOI:10.1124/dmd.121.000439

2021 Drug metabolism and disposition: the biological fate of chemicals

* Investigating the Utility of Humanized Pregnane X Receptor-Constitutive Androstane Receptor-CYP3A4/7 Mouse Model to Assess CYP3A-Mediated Induction.

- Clinical induction liability is assessed with human hepatocytes. However, underpredictions in the magnitude of clinical induction have been reported. Unfortunately, in vivo studies in animals do not provide additional insight because of species differences in drug metabolizing enzymes and their regulatory pathways. To circumvent this limitation, transgenic animals expressing human orthologs were developed. The aim of this work was to investigate the utility of mouse models expressing human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 (Tg-Composite) in evaluating clinical induction. Rifampin, efavirenz, and pioglitazone, which were employed to represent strong, moderate, and weak inducers, were administered at multiple doses to Tg-Composite animals. In vivo CYP3A activity was monitored by measuring changes in the exposure of the CYP3A probe substrate triazolam. After the in vivo studies, microsomes were prepared from their livers to measure changes of in vitro CYP3A4 activity. In both in vivo and in vitro, distinction of clinic induction was recapitulated as rifampin yielded the greatest inductive effect followed by efavirenz and pioglitazone. Interestingly, with rifampin, in vivo CYP3A activity was approximately 4-fold higher than in vitro activity. Conversely, there was no difference between in vivo and in vitro CYP3A activity with efavirenz. These findings are consistent with the report that, although rifampin exhibits differential inductive effects between the intestines and liver, efavirenz does not. These data highlight the promise of transgenic models, such as Tg-Composite, to complement human hepatocytes to enhance the translatability of clinical induction as well as become a powerful tool to further study mechanisms of drug disposition. SIGNIFICANCE STATEMENT: Underprediction of the magnitude of clinical induction when using human hepatocytes has been reported, and transgenic models may improve clinical translatability. The work presented here showcases the human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 model, which was able to recapitulate the magnitude of clinical induction and to differentiate tissue-dependent induction observed with rifampin but not with efavirenz. These results not only foreshadow the potential application of such transgenic models in assessing clinical induction but also in further investigation of the mechanism of drug disposition.

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(1)69 and	(13)5 are	(25)3 interventions	(37)2 effect;
(2)46 of	(14)5 or	(26)3 limitations	(38)2 for
(3)45 in	(15)5 relationship	(27)3 models	(39)2 has
(4)44 null	(16)5 with	(28)3 opportunities	(40)2 increased
(5)14 was	(17)4 and/or	(29)3 programs	(41)2 levels
(6)13 against	(18)4 at	(30)3 sedentary	(42)2 levels,
(7)12 (PA)	(19)4 may	(31)3 that	(43)2 plays
(8)10 is	(20)3 (PA),	(32)3 through	(44)2 programmes
(9)7 as	(21)3 advice	(33)2 appears	(45)2 using
(10)6 by	(22)3 but	(34)2 assessment
(11)6 during	(23)3 changes	(35)2 counselling
(12)6 on	(24)3 compared	(36)2 differentiation

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--- WordNet output for activity --- =>活動, 活躍, 働き, 動き, 活気 Overview of noun activity The noun activity has 6 senses (first 3 from tagged texts) 1. (43) activity -- (any specific behavior; "they avoided all recreational activity") 2. (36) action, activity, activeness -- (the state of being active; "his sphere of activity"; "he is out of action") 3. (13) bodily process, body process, bodily function, activity -- (an organic process that takes place in the body; "respiratory activity") 4. activity -- ((chemistry) the capacity of a substance to take part in a chemical reaction; "catalytic activity") 5. natural process, natural action, action, activity -- (a process existing in or produced by nature (rather than by the intent of human beings); "the action of natural forces"; "volcanic activity") 6. activeness, activity -- (the trait of being active; moving or acting rapidly and energetically; "the level of activity declines with age") --- WordNet end ---