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Titolo:
The lipophilicity, pharmacokinetics, and cellular uptake of different chemically-modified tetracyclines (CMTs)
Autore:
Liu, Y; Ramamurthy, NS; Marecek, J; Lee, HM; Chen, JL; Ryan, ME; Rifkin, BR; Golub, LM;
Indirizzi:
SUNY Stony Brook, Sch Dent Med, Dept Oral Biol & Pathol, Stony Brook, NY 11794 USA SUNY Stony Brook Stony Brook NY USA 11794 thol, Stony Brook, NY 11794 USA SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA SUNY Stony Brook Stony Brook NY USA 11794 Chem, Stony Brook, NY 11794 USA NYU, Sch Dent, Div Basic Sci, New York, NY 10011 USA NYU New York NY USA 10011 Sch Dent, Div Basic Sci, New York, NY 10011 USA
Titolo Testata:
CURRENT MEDICINAL CHEMISTRY
fascicolo: 3, volume: 8, anno: 2001,
pagine: 243 - 252
SICI:
0929-8673(200102)8:3<243:TLPACU>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
MODIFIED NONANTIMICROBIAL TETRACYCLINE; COLLAGENASE ACTIVITY; CREVICULAR FLUID; GINGIVAL; DRUGS; BONE; BREAKDOWN;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
20
Recensione:
Indirizzi per estratti:
Indirizzo: Liu, Y SUNY Stony Brook, Sch Dent Med, Dept Oral Biol & Pathol, Stony Brook, NY 11794 USA SUNY Stony Brook Stony Brook NY USA 11794 tony Brook, NY 11794 USA
Citazione:
Y. Liu et al., "The lipophilicity, pharmacokinetics, and cellular uptake of different chemically-modified tetracyclines (CMTs)", CURR MED CH, 8(3), 2001, pp. 243-252

Abstract

CMTs are analogs of tetracyclines, which are chemically modified to eliminate their antimicrobial efficacy but which retain their inhibitory activityagainst matrix metall oproteinases. 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 mi 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 peakconcentrations (C-max) in rat sera 1-12 hours after oral administration ofCMTs -1, -2,-3, -3,-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 mug/ml, respectively. Their in vivo half-lives (t(1/2)) were ii, 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 weretested 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 (r(2)=0.95, P<0.001). Since CMT-8. as well as CMTs-3 and -1, consistentlyexhibited the greatest in vivo efficacy in animal models of tissue breakdown, this may reflect, at least in part, their favorable pharmacokinetics and tissue uptake.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 08:58:35