The lipophilicity, pharmacokinetics, and cellular uptake of different chemically-modified tetracyclines (CMTs)

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
Citations number
Categorie Soggetti
Pharmacology & Toxicology
Journal title
ISSN journal
0929-8673 → ACNP
Year of publication
243 - 252
SICI code
CMTs are analogs of tetracyclines, which are chemically modified to elimina te their antimicrobial efficacy but which retain their inhibitory activity against matrix metall oproteinases. These compounds have been found to inhi bit connective tissue breakdown in animal models of diseases such as period ontitis, arthritis and cancer, because CMTs exhibit different in vivo effic acy in these various models of disease, the current study compared their ph armacokinetics and other properties as follows: Adult male Sprague-Dawley r ats were administered by oral gavage a single dose of 5mg of different CMTs suspended in 1 mi 2% carboxymethyl-cellulose, and blood samples were colle cted from 1-48 hours after dosing. The sera were extracted, then analyzed b y 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, -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 CMT s-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 tha t CMT-2, -5, and -6 had the lowest partition coefficients using this organi c solvent, while CMT-3 was the most lipophilic. The lipophilicity of the di fferent CMTs was also positively correlated (r(2)=0.767, P<0.05) to peak se rum 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, consistently exhibited the greatest in vivo efficacy in animal models of tissue breakdow n, this may reflect, at least in part, their favorable pharmacokinetics and tissue uptake.