Permeability of articular cartilage to matrix metalloprotease inhibitors.
OBJECTIVE
To develop an in vitro cartilage permeation model for cartilage permeability study and to evaluate the effects of molecular hydrophilicity and cartilage location on the permeability of articular cartilage to matrix metalloprotease inhibitors.


METHODS
An in vitro cartilage permeation model was developed and utilized to determine the permeability of articular cartilage to the matrix metalloprotease inhibitors of different hydrophilicity. Permeability coefficients were obtained by measuring the steady-state flux of the inhibitor compounds. HPLC methods were also developed and employed for the analysis of drug levels in assay media.


RESULTS
The relationship between permeability and hydrophilicity of drug molecules was examined. Results indicated that the permeability coefficient increased with increasing hydrophilicity of the molecule. Additionally, the relationship between the permeability and the location of the cartilage section within the animal joint was investigated. Our results showed that the drug molecules penetrated faster in the surface layer cartilage than in the deep layer cartilage.


CONCLUSIONS
Increasing the hydrophilicity of a molecule would increase its permeability across articular cartilage. The in vitro cartilage permeation model developed could be used to rank order drug compounds according to their cartilage permeability profiles and to aid in drug selection and development.
Peng
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SX
The Procter & Gamble Company, Health Care Research Center, Mason, Ohio 45040, USA. pengsx@pg.com
VonBargen
E C
EC
Bornes
D M
DM
Pikul
S
S
D000818:Animals; D001692:Biological Transport; D002358:Cartilage, Articular / Q000378:metabolism*; D002417:Cattle; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007596:Joints / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008954:Models, Biological; D010539:Permeability; D014867:Water / Q000737:chemistry
D004791:Enzyme Inhibitors; D014867:Water; D008666:Metalloendopeptidases