In vitro-in vivo correlation on delivery of drug candidates to articular cartilage.
OBJECTIVE
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.


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.


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.
Wang
Qin
Q
Discovery Pharmacokinetics, Wyeth Research, One Burtt Rd, Andover, Massachusetts 01810, USA. qin.wang@biogenidec.com
Glasson
Sonya
S
Raut
Uma
U
Emerson
Jamie
J
Blanchet
Tracey
T
Bridson
Gary
G
Sheldon
Richard
R
Mollova
Nevena
N
Morris
Elisabeth
E
Xu
Xin
X
Patel
Vikram S
VS
D000818:Animals; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002358:Cartilage, Articular / Q000737:chemistry; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005079:Excipients; D007269:Injections, Intra-Arterial; D007596:Joints / Q000737:chemistry; D008297:Male; D013058:Mass Spectrometry; D061965:Matrix Metalloproteinase Inhibitors; D011485:Protein Binding; D011817:Rabbits; D012709:Serum Albumin / Q000494:pharmacology; D013582:Synovial Fluid / Q000378:metabolism
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D005079:Excipients; D061965:Matrix Metalloproteinase Inhibitors; D012709:Serum Albumin