Abstract：
PURPOSE:A series of studies was conducted to evaluate the preclinical pharmacokinetics of SB-239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl] imidazole), a potent and selective p38 MAP kinase inhibitor. METHODS:SB-239063 was administered both i.v. and p.o. in the rat, dog, cynomolgus monkey, and rhesus monkey, with standard pharmacokinetic parameters generated from the concentration vs. time data. RESULTS:Initial rat studies suggested possible nonlinear disposition, however, assay refinement revealed an in vivo trans-cis isomerization of SB-239063 to a metabolite with nearly identical chromatographic and mass spectral properties. SB-239063 exhibited low to moderate clearance and good bioavailability in the rat and dog, but poor bioavailability in the cynomolgus monkey. Substantial in vivo trans-cis isomerization occurred in the rat and cynomolgus monkey, but occurred to a far lesser extent in the dog. The isomerization reaction was reversible, with a recycled fraction of 0.20 and 0.0003 in the rat and cynomolgus monkey, respectively. In the rhesus monkey, bioavailability was also poor. but no in vivo isomerization was observed. Conclusions. These studies demonstrate the necessity of exercising vigilance in conducting high-throughput analytical method development, and the importance of using a variety of preclinical species when evaluating the disposition of new drug candidates.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Ward KW,Proksch JW,Azzarano LM,Salyers KL,McSurdy-Freed JE,Molnar TM,Levy MA,Smith BRdoi
10.1023/a:1013002414678subject
Has Abstractpub_date
2001-09-01 00:00:00pages
1336-44issue
9eissn
0724-8741issn
1573-904Xjournal_volume
18pub_type
杂志文章abstract：PURPOSE:The objective of this study was to evaluate the in vivo consequences of glycyl-glutamate coadministration on gabapentin oral absorption. METHODS:Rats were administered gabapentin (10 mg/kg plus radiotracer) by gastric gavage, in the absence and presence of dipeptides, and by intravenous administration. Serial ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
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更新日期：2013-09-01 00:00:00
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journal_title：Pharmaceutical research
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doi：10.1023/a:1011012822437
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更新日期：2013-06-01 00:00:00
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更新日期：2008-02-01 00:00:00
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更新日期：2011-01-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2005-07-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018984121415
更新日期：1993-03-01 00:00:00
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
doi：10.1023/a:1015963128124
更新日期：1989-09-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1011921031564
更新日期：1998-11-01 00:00:00
abstract：PURPOSE:Paclitaxel is a first-line drug for the therapy of lung cancer, however, drug resistance is a serious limiting factor, related to overexpression of anti-apoptotic proteins like survivin. To overcome this phenomenon, developing novel ultrasound responsive nanobubbles - nanosized drug delivery system- for the del...
journal_title：Pharmaceutical research
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更新日期：2020-08-05 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1007657109012
更新日期：2000-12-01 00:00:00
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journal_title：Pharmaceutical research
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doi：10.1007/s11095-017-2224-1
更新日期：2017-10-01 00:00:00
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journal_title：Pharmaceutical research
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doi：10.1023/a:1015865319250
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
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更新日期：2014-03-01 00:00:00
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pub_type： 杂志文章
doi：10.1007/s11095-005-7415-5
更新日期：2005-11-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2009-01-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016225707807
更新日期：1995-09-01 00:00:00
abstract：PURPOSE:To investigate the effect of surface functionalization of mesoporous silica nanoparticles (MSN) on crystallization, loading, release and activity of mitoxantrone (MTX). METHODS:Thiol-, amine-, and mixed thiol/amine-functionalized MSN were synthesized and characterized by electron microscopy, thermogravimetry, ...
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pub_type： 杂志文章
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更新日期：2012-09-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2003-04-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016205520044
更新日期：1995-11-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1007521016985
更新日期：2000-05-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
doi：10.1007/s11095-016-2089-8
更新日期：2017-03-01 00:00:00
