title: Biodistribution of etanercept to tissues and sites of inflammation in arthritic rats.
abstract: Many monoclonal antibodies (mAbs) and other protein drugs have targets usually residing within tissues, making tissue concentrations of mAbs relevant to their pharmacologic effects. Therefore, knowledge of tissue distribution kinetics is important to better understand their pharmacokinetics and pharmacodynamics. The tissue distribution of mAbs is affected by many physiologic factors that may be altered in disease status. In the present work, we studied the tissue distribution kinetics of the fusion protein etanercept in inflamed joint tissues and examined the impact of inflammation on the tissue distribution of etanercept. Etanercept concentration profiles in plasma, blister fluid, and different tissues were obtained from healthy and collagen-induced arthritic (CIA) rats by use of a fluorescence quantification method via IRDye800CW labeling. Stepwise minimal and full physiologically based pharmacokinetic (PBPK) approaches were applied to characterize the distribution kinetics of etanercept in tissues in healthy and diseased animals. Etanercept exhibited modest tissue access (tissue/plasma area under the concentration curve [AUC] ratios 0.03-0.15 and estimated tissue reflection coefficients [σ] of 0.6-1.0), but with good penetration into arthritic paws (tissue/plasma AUC ratio 0.23 and σ 0.36). Etanercept exposure in the inflamed paws of CIA rats was approximately 3-fold higher than in normal paws taken from either CIA or healthy rats (tissue/plasma AUC ratios 0.23 versus 0.07 and σ 0.36 versus 0.71). The tissue distribution kinetics of etanercept in arthritic paws were well characterized with PBPK modeling approaches. Etanercept shows good penetration to arthritic paws in CIA rats. Our study indicates that inflammation produced increased tissue distribution of etanercept in CIA rats.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, (X.C., D.C.D., R.R.A., W.J.J.), Department of Biological Sciences (D.C.D., R.R.A.), and New York State Center of Excellence in Bioinformatics and Life Sciences (R.R.A., W.J.J.), State University of New York at Buffalo, Buffalo, New York.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, (X.C., D.C.D., R.R.A., W.J.J.), Department of Biological Sciences (D.C.D., R.R.A.), and New York State Center of Excellence in Bioinformatics and Life Sciences (R.R.A., W.J.J.), State University of New York at Buffalo, Buffalo, New York.
authors.forename: Debra C
authors.initials: DC
authors.lastname: DuBois
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, (X.C., D.C.D., R.R.A., W.J.J.), Department of Biological Sciences (D.C.D., R.R.A.), and New York State Center of Excellence in Bioinformatics and Life Sciences (R.R.A., W.J.J.), State University of New York at Buffalo, Buffalo, New York.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Almon
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, (X.C., D.C.D., R.R.A., W.J.J.), Department of Biological Sciences (D.C.D., R.R.A.), and New York State Center of Excellence in Bioinformatics and Life Sciences (R.R.A., W.J.J.), State University of New York at Buffalo, Buffalo, New York wjjusko@buffalo.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001557:Benzenesulfonates; D001682:Biological Availability; D001768:Blister / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D000068800:Etanercept / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005456:Fluorescent Dyes; D005528:Foot; D007211:Indoles; D007596:Joints / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008196:Lymph / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D042601:Lymphatic Vessels / Q000187:drug effects / Q000276:immunology; D008297:Male; D008954:Models, Biological; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D013582:Synovial Fluid / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001557:Benzenesulfonates; D005456:Fluorescent Dyes; C562366:IRDye 800CW; D007211:Indoles; D011993:Recombinant Fusion Proteins; D000068800:Etanercept
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