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

Abstract

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 FM) 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 FLM prior to dosage, peaked at 26.2 FLM 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.

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

“…403 Peak concentrations of the albumin conjugate were also variable after single doses, and exceeded peak penicillamine concentrations in samples collected more than 3 hours postdose (Joyce et al 1991). Mean steady-state concentrations (± SEM) of penicillamine have been reported to be 5.4 ± 1.2 Jlmol/L, and the concentration of the albumin conjugate was about 5 times as high (Joyce & Day 1990). These variable concentrations of reduced penicillamine, and the albumin conjugate reservoir, may contribute to the variable clinical response noted with this drug.…”

“…The half-life of the disu1phide conjugate with albumin was reported to be approximately 36 hours (Joyce & Day 1990;Joyce et al 1991), compared with a half-life reported for penicillamine itself of 0.6 to 3 hours (Bergstrom et al 1981;Brooks et al 1984;Joyce & Day 1990;Osman et al 1983).…”

“…Both penicillamine and the albumin conjugate have been quantified in the synovial fluid of these individuals (Joyce & Day 1990). Transport of the drug attached to albumin is thought to be an important mechanism of transport across the synovial membrane.…”

Practical Aspects of the Ligand-Binding and Enzymatic Properties of Human Serum Albumin.

“…For example, N-acetyl-L-cysteine (and L-cysteine) binds to albumin in plasma; the interaction can be quantitated by a high-performance liquid chromatographic (HPLC) method using hexaiodoplatinate. 36) Furthermore, D-penicillamine, 32,37) captopril, 32,33) meso-2,3-dimercaptosuccinate, 38) and SA3786 (a bucillamine derivative) 39) bind to albumin in the serum of patients receiving these drugs. Interestingly, the reactivity in patient sera is much higher than that found in albumin solutions 33) and in sera of healthy volunteers.…”

A Dangerous Vitious Circle of the Neonatal Brain in Bilirubin- Induced Neurologic Dysfunction (BIND)

“…Low molecular weight disulfides are the major products of D-PA metabolism in humans. 9 The oxidation of D-PA in vivo may also important in the mode of action of the drug through simultaneous reduction of the ROS and reactive nitrogen species (RNS). Consequently, D-PA fulfils the criteria of a hybrid drug in the neonatal period by its ability to modulate both oxidative stress and NO pathway, and can be a neuroprotective agent in the pathophysiology of neurologic dysfunction (Figure 1).…”