Document Detail


Altered brain penetration of diclofenac and mefenamic acid, but not acetaminophen, in Shiga-like toxin II-treated mice.
MedLine Citation:
PMID:  15821337     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
It is well accepted that bacterial and virus infections elevate the levels of cytokines in serum and cerebrospinal fluids. Such high levels of cytokines might alter the integrity of the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCSFB), subsequently affecting brain penetration of drugs. However, few reports have addressed this issue. Thus, we investigated brain penetration of cyclooxygenase (COX) inhibitors, commonly used as antipyretics, in mice treated with Shiga-like toxin II (SLT-II) derived from E. coli O157:H7, which significantly elevates cytokine levels. As antipyretics, we used diclofenac, mefenamic acid, and acetaminophen. We found that SLT-II significantly increased the brain-to-plasma concentration ratio (Kp) of diclofenac and mefenamic acid, but not of acetaminophen. Moreover, the Kp of diclofenac and mefenamic acid was increased by probenecid, an anionic compound. These results suggest that efflux anion transporters might be involved in the transport of diclofenac and mefenamic acid. Western blot analysis revealed that SLT-II decreased the expression of organic anion transporter-3, an efflux transporter located on the BBB and/or BCSFB. Taken together, these results suggest that SLT-II and/or SLT-II-stimulated cytokines might change brain penetration of drugs and could possibly increase the risk of their side-effects by altering the expression of transporters.
Authors:
Masaya Fukuda; Kiyoyuki Kitaichi; Fumie Abe; Yohei Fujimoto; Kenji Takagi; Kenzo Takagi; Tsuneo Morishima; Takaaki Hasegawa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-04-09
Journal Detail:
Title:  Journal of pharmacological sciences     Volume:  97     ISSN:  1347-8613     ISO Abbreviation:  J. Pharmacol. Sci.     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-04-20     Completed Date:  2005-09-29     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  101167001     Medline TA:  J Pharmacol Sci     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  525-32     Citation Subset:  IM    
Affiliation:
Department of Medical Technology, Nagoya University School of Health Sciences, Japan.
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MeSH Terms
Descriptor/Qualifier:
Acetaminophen / pharmacokinetics
Analgesics, Non-Narcotic / pharmacokinetics,  toxicity
Animals
Blood-Brain Barrier / drug effects*
Brain / drug effects*,  metabolism*
Cyclooxygenase Inhibitors / pharmacokinetics,  toxicity
Cytokines / metabolism
Diclofenac / pharmacokinetics*,  toxicity
Male
Mefenamic Acid / pharmacokinetics*,  toxicity
Mice
Organic Anion Transporters, Sodium-Independent / metabolism
Probenecid / pharmacology
Protein Binding / drug effects
Shiga Toxin 2 / toxicity*
Chemical
Reg. No./Substance:
0/Analgesics, Non-Narcotic; 0/Cyclooxygenase Inhibitors; 0/Cytokines; 0/Organic Anion Transporters, Sodium-Independent; 0/Shiga Toxin 2; 0/organic anion transport protein 3; 103-90-2/Acetaminophen; 15307-86-5/Diclofenac; 57-66-9/Probenecid; 61-68-7/Mefenamic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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