Document Detail


Pharmacokinetics, pharmacodynamics and toxicities of methotrexate in healthy and collagen-induced arthritic rats.
MedLine Citation:
PMID:  23456770     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPG(n)) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen-induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post-induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPG(n) in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple-doses, RBC MTX reached steady-state (82.4 nm) within 4 days. The MTXPG(2) and MTXPG(3) in RBC kept increasing until the end of the study, attaining 12.5 and 17.7 nm. Significant weight loss was observed after dosing with 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing with 0.3 mg/kg/2 days. A pharmacokinetic/pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX and RBC MTXPG(n) concentrations, and paw size was developed using naïve data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. Methotrexate showed modest (I(maxd) = 0.16) but sensitive (IC(50d) = 0.712 nm) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of the effects of methotrexate on rheumatoid arthritis.
Authors:
Dong-Yang Liu; Hoi-Kei Lon; Yan-Lin Wang; Debra C DuBois; Richard R Almon; William J Jusko
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-07
Journal Detail:
Title:  Biopharmaceutics & drug disposition     Volume:  34     ISSN:  1099-081X     ISO Abbreviation:  Biopharm Drug Dispos     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-15     Completed Date:  2013-12-10     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  7911226     Medline TA:  Biopharm Drug Dispos     Country:  England    
Other Details:
Languages:  eng     Pagination:  203-14     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 John Wiley & Sons, Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antirheumatic Agents / pharmacokinetics,  pharmacology*,  toxicity
Arthritis, Experimental / drug therapy*,  pathology
Arthritis, Rheumatoid / drug therapy*,  pathology
Body Weight / drug effects
Collagen Type II / toxicity
Disease Progression
Dose-Response Relationship, Drug
Edema / drug therapy,  pathology
Inhibitory Concentration 50
Male
Methotrexate / pharmacokinetics,  pharmacology*,  toxicity
Models, Biological
Rats
Rats, Inbred Lew
Swine
Time Factors
Grant Support
ID/Acronym/Agency:
GM24211/GM/NIGMS NIH HHS; R37 GM024211/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antirheumatic Agents; 0/Collagen Type II; YL5FZ2Y5U1/Methotrexate
Comments/Corrections

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