ABSTRACT
Purpose
In the treatment of osteoarthritis (OA), some of the therapeutic approaches require delivery of drug(s) to the diseased cartilage. Presence of adequate drug levels in the cartilage is one of the important criteria in selection and ranking of lead compounds. The purpose of this study was to investigate the correlation in cartilage compound levels between in vitro experiments and in vivo animal studies.
Materials and Methods
Bovine cartilage samples were incubated with test compounds of various concentrations in a culture medium, in the absence or presence of 25 mg/ml of serum albumin which served as an artificial synovial fluid (SF). The test compounds were also dosed to rabbits, the animal model used for efficacy studies, over a six-week treatment period. Test article concentrations in plasma, SF, and cartilage were determined by LC/MS/MS analysis.
Results and Conclusions
A correlation in cartilage drug concentration was observed between in vitro and in vivo studies. Plasma protein binding and the test article’s affinity to cartilage were the major determining factors for drug delivery to cartilage in vivo.
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Abbreviations
- \({\text{AUC}}_{{\text{cartilage}}}^{} \) :
-
area under the compound concentration-time curve in cartilage
- \({\text{AUC}}_{{\text{diseased\_SF}}}^{{\text{unbound}}} \) or \({\text{AUC}}_{{\text{diseased\_SF}}}^{{\text{total}}} \) :
-
area under the unbound or total compound concentration-time curve in diseased SF
- \({\text{AUC}}_{{\text{plasma}}}^{{\text{unbound}}} \) or \({\text{AUC}}_{{\text{serum}}}^{{\text{unbound}}} \) :
-
area under the unbound compound concentration-time curve in plasma or serum
- \({\text{AUC}}_{{\text{SF}}}^{{\text{unbound}}} \)or \({\text{AUC}}_{{\text{SF}}}^{{\text{total}}} \) :
-
area under the unbound or total compound concentration-time curve in SF
- \({\text{AUC}}_{{\text{plasma}}}^{{\text{total}}} \) or \({\text{AUC}}_{{\text{serum}}}^{{\text{total}}} \) :
-
area under the total compound concentration-time curve in plasma or serum
- \(C_{cartilage}^{} \) :
-
compound concentration in cartilage
- \(C_{{\text{plasma}}}^{} \) or \(C_{{\text{plasma}}}^{{\text{total}}} \) or \({}^{{\text{drug}}}C_{{\text{plasma}}}^{{\text{total}}} \) or \(C_{{\text{serum}}}^{} \) or \(C_{{\text{serum}}}^{{\text{total}}} \) :
-
total compound concentration in plasma or serum
- \(C_{{\text{plasma}}}^{{\text{protein}}} \) or \(C_{{\text{serum}}}^{{\text{protein}}} \) :
-
total protein concentration in plasma or serum
- \(C_{{\text{SF}}}^{} \) or \(C_{{\text{SF}}}^{{\text{total}}} \) or \({}^{{\text{drug}}}C_{{\text{SF}}}^{{\text{total}}} \) or \(C_{{\text{healthy\_SF}}}^{{\text{total}}} \) :
-
total compound concentration in SF
- \(C_{{\text{diseased\_SF}}}^{{\text{unbound}}} \) or \(C_{{\text{diseased\_SF}}}^{{\text{total}}} \) :
-
unbound or total compound concentration in diseased SF
- \(C_{{\text{plasma}}}^{{\text{unbound}}} \) or \([C_{{\text{plasma}}} \times \% _{{\text{free}} - {\text{fraction}}} ]\) or \(C_{{\text{serum}}}^{{\text{unbound}}} \) :
-
unbound compound concentration in plasma or serum
- \(C_{{\text{SF}}}^{{\text{unbound}}} \) or \({}^{{\text{drug}}}C_{{\text{SF}}}^{{\text{unbound}}} \) or \(C_{{\text{healthy\_SF}}}^{{\text{unbound}}} \) :
-
unbound compound concentration in synovial fluid (SF)
- \({}^{{\text{drug}}}C_{{\text{SF}}}^{{\text{bound\_to\_proteins}}} \) or \({}^{{\text{drug}}}C_{{\text{plasma}}}^{{\text{bound\_to\_proteins}}} \) :
-
SF or plasma compound concentrations that associated with SF or plasma proteins
- %free-fraction :
-
percentage of unbound compound in plasma
- SF:
-
synovial fluid
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Acknowledgements
We thank Jessica Doherty, Cindy Clark, Amy Ignatowicz, Terrie Cunliffe-Beamer, and Glen Pedneault for performing in vivo studies.
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Wang, Q., Glasson, S., Raut, U. et al. In Vitro–In Vivo Correlation on Delivery of Drug Candidates to Articular Cartilage. Pharm Res 25, 1641–1646 (2008). https://doi.org/10.1007/s11095-008-9557-8
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DOI: https://doi.org/10.1007/s11095-008-9557-8