D‐penicillamine and D‐penicillamine‐protein disulphide in plasma and synovial fluid of patients with rheumatoid arthritis.

1. The plasma pharmacokinetics of D‐penicillamine (D‐pen) and D‐ penicillamine‐albumin disulphide (D‐pen‐alb) were examined over a dosage interval in six patients with rheumatoid arthritis. In two of these, 24 h synovial fluid profiles of D‐pen and D‐pen‐alb were also obtained. 2. D‐pen was undetectable in plasma at the beginning of the study. The peak concentration (5.4 +/− 1.2 microM) occurred at between 45 min and 2 h and the mean elimination half‐life was 0.6 h. D‐pen‐alb, however, was present at a mean plasma concentration of 19.1 microM prior to dosage, peaked at 26.2 microM and was eliminated with a half‐ life of 40 h. 3. D‐pen concentrations in synovial fluid rose more slowly and peaked lower than in plasma. D‐pen‐alb was present in synovial fluid of the patients at 50.1% and 83.6%, respectively, of the simultaneous plasma concentration prior to dosage. Concentrations varied during the study interval, corresponding to changes in plasma concentrations. 4. These results demonstrate that D‐pen forms stable conjugates with protein in treated patients. The presence of D‐pen‐alb in relatively high concentrations throughout the dosage interval contrasts with the low concentrations and rapid elimination of D‐pen. Both D‐pen and D‐pen‐alb were also shown to be present at the putative site of drug action (the inflamed synovial joint) in concentrations lower than those in plasma.