D-penicillamine metabolism in an in-vivo model of inflamed synovium.
Oxidation to disulphides is the chief metabolic transformation of D-penicillamine (D-pen) in patients with rheumatoid arthritis. Oxidation also occurs in many biological fluids in-vitro. Reduction of oxygen species may accompany the oxidation of D-pen under appropriate conditions and may mediate the anti-rheumatic action of D-pen. The transformation of D-pen therefore was examined in an in-vivo model of inflamed synovium. Subcutaneous air-pouches of groups of rats were treated with saline, 10% serum or 10% zymosan activated serum (ZAS). The transformation of D-pen to low molecular weight (LMW) metabolites and protein conjugates within the pouch was then assessed. The concentrations of total protein were significantly higher in the serum and ZAS-treated groups than in the saline-treated group and the inflammatory cell counts were significantly higher in the ZAS-treated group than in either of the other groups, as expected. D-pen oxidised rapidly to LMW metabolites and smaller amounts of D-pen-protein conjugate (D-pen-protein) in the air pouches of all animals. The rates of oxidation to LMW metabolites were greater in the ZAS-treated animals than the saline-treated group (p less than 0.005). The concentrations of D-pen-protein conjugate were also greater for the serum-treated and ZAS-treated animals than for the saline controls (p less than 0.005 in each case) at all times. Oxidation of D-pen therefore occurs at this site of inflammation and is influenced by local conditions. This may be important to understanding the forms in which D-pen exists in inflamed synovial joints and the way it may exert its antirheumatic activity.
Joyce
D A
DA
Department of Pharmacology, University of Western Australia, Nedlands.
Forrest
M J
MJ
Brooks
P M
PM
D000818:Animals; D008297:Male; D010396:Penicillamine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013583:Synovial Membrane / Q000378:metabolism; D013585:Synovitis / Q000378:metabolism*; D013997:Time Factors; D015054:Zymosan
D015054:Zymosan; D010396:Penicillamine