Linked Life Data

11172678

Source:http://linkedlifedata.com/resource/pubmed/id/11172678

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2001-2-22
pubmed:abstractText
CMTs are analogs of tetracyclines, which are chemically modified to eliminate their antimicrobial efficacy but which retain their inhibitory activity against matrix metalloproteinases. These compounds have been found to inhibit connective tissue breakdown in animal models of diseases such as periodontitis, arthritis and cancer. Because CMTs exhibit different in vivo efficacy in these various models of disease, the current study compared their pharmacokinetics and other properties as follows: Adult male Sprague-Dawley rats were administered by oral gavage a single dose of 5mg of different CMTs suspended in 1 ml 2% carboxymethyl-cellulose, and blood samples were collected from 1-48 hours after dosing. The sera were extracted, then analyzed by HPLC using a C-18 reverse-phase column. The results showed that the peak concentrations (C(max)) in rat sera 1-12 hours after oral administration of CMTs -1, -2,-3, -4,-5,-6,-7,-8 and doxycycline were 5.5, 0.7, 4.6, 6.2, 0.8, 0.7, 9.0 (note: the 3 peaks detected for CMT-7 were combined), 15.0 and 0.9 microg/ml, respectively. Their in vivo half-lives (t(1/2)) were 11, 5, 22, 11, 32, 15, 37, 38, and 17 hours, respectively. Of the anticollagenase CMTs tested, CMT-8 showed the greatest C(max) and t(1/2)values, followed by CMTs-3, -1, -4, and perhaps -7; CMTs-2, -5, and -6 exhibited much lower levels in serum. The relative lipophilicities of the 8 CMTs and doxycycline were tested by examining their extractability in octanol. The results showed that CMT-2, -5, and -6 had the lowest partition coefficients using this organic solvent, while CMT-3 was the most lipophilic. The lipophilicity of the different CMTs was also positively correlated (r(2)=0.767, P<0.05) to peak serum concentrations (C(max)), but not to their serum half-lives (r(2)=0.25,P=0.49). This property of the different CMTs was also found to be positively correlated to their ability to enter into human whole blood cells in vitro (r2=0.95, P<0.001). Since CMT-8, as well as CMTs-3 and -1, consistently exhibited the greatest in vivo efficacy in animal models of tissue breakdown, this may reflect, at least in part, their favorable pharmacokinetics and tissue uptake.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0929-8673
pubmed:author
pubmed:issnType
Print
pubmed:volume
8
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
243-52
pubmed:dateRevised
2007-2-12
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
The lipophilicity, pharmacokinetics, and cellular uptake of different chemically-modified tetracyclines (CMTs).
pubmed:affiliation
Department of Oral Biology and Pathology, School of Dental Medicine, State University of New York, at Stony Brook, New York, NY 11794, USA.
pubmed:publicationType
Journal Article