Netter P, Bannwarth B, Péré P, Nicolas A
Département de Pharmacologie Clinique, Université de Nancy I.
Clin Pharmacokinet. 1987 Nov;13(5):317-33. doi: 10.2165/00003088-198713050-00003.
Penicillamine exists as 2 stereoisomers, but only the D-isomer is used therapeutically. Its chemical reactivity derives from its functional groups, of which the thiol group seems the most important. It is difficult to determine penicillamine in biological fluids because of its instability, the presence of endogenous compounds with a thiol function, and the various chemical forms in which it occurs, namely reduced free penicillamine, penicillamine bound to proteins, and internal (P-S-S-P) and mixed (P-S-S-C) disulphides. The earliest assay methods (colourimetry, isotopic methods, gas-phase chromatography) were neither sensitive nor specific. High performance liquid chromatography with electrochemical detection has led to a more specific assay for D-penicillamine, with detection based on either derivatisation reactions or on electro-oxidisation of the thiol function. With dual-electrode detectors (Au/Hg) disulphides can be assayed directly. D-penicillamine is absorbed rapidly but incompletely (40 to 70%) in the intestine, with wide interindividual variations. Food, antacids and, in particular, iron reduce absorption of the drug. Its bioavailability is also dramatically decreased in patients with malabsorption states. The peak plasma concentration occurs at 1 to 3 hours after ingestion, regardless of dose, and is of the order of 1 to 2 mg/L after an oral dose of 250 mg; some investigators have reported a double peak in plasma, which is probably not due to an enterohepatic cycle. The concentration in plasma then decreases rapidly, generally following a biphasic curve. When long term treatment is discontinued, there is a slow elimination phase lasting 4 to 6 days, which suggests that there is a 'deep compartment' or 'slow pool of the drug reversibly bound to tissues', particularly the skin. This may explain the persistence of its therapeutic effect and the occurrence of undesirable side effects after treatment has been stopped. During long term treatment plasma concentrations are highly variable between individuals. They do not seem to be correlated with the activity or the toxicity of D-penicillamine in patients with rheumatoid arthritis. More than 80% of plasma D-penicillamine is bound to proteins, particularly albumin. The rest is mainly in the free reduced form or as disulphides. Only a small portion of the dose is metabolised in the liver to S-methyl-D-penicillamine. The route of elimination is mainly renal; disulphides represent the main compounds found in the urine. Faecal excretion corresponds mainly to the non-absorbed fraction of the drug.
青霉胺有2种立体异构体，但只有D - 异构体用于治疗。其化学反应性源于其官能团，其中硫醇基团似乎最为重要。由于青霉胺不稳定、存在具有硫醇功能的内源性化合物以及它所呈现的各种化学形式，即还原型游离青霉胺、与蛋白质结合的青霉胺以及内源性（P - S - S - P）和混合型（P - S - S - C）二硫化物，所以很难在生物体液中测定青霉胺。最早的检测方法（比色法、同位素法、气相色谱法）既不灵敏也不特异。具有电化学检测功能的高效液相色谱法已实现了对D - 青霉胺更特异的检测，检测基于衍生化反应或硫醇功能的电氧化。使用双电极检测器（金/汞）可直接检测二硫化物。D - 青霉胺在肠道中吸收迅速但不完全（40%至70%），个体间差异很大。食物、抗酸剂，尤其是铁会降低该药物的吸收。在吸收不良状态的患者中，其生物利用度也会显著降低。无论剂量如何，口服后1至3小时出现血浆峰浓度，口服250mg后血浆峰浓度约为1至2mg/L；一些研究人员报告血浆中有双峰，这可能并非由于肝肠循环。随后血浆浓度迅速下降，一般呈双相曲线。长期治疗停药后，有一个持续4至6天的缓慢消除期，这表明存在一个“深部隔室”或“药物与组织可逆结合的缓慢池”，尤其是皮肤。这可能解释了其治疗效果的持续性以及停药后不良副作用的发生。长期治疗期间，个体间血浆浓度差异很大。它们似乎与类风湿性关节炎患者中D - 青霉胺的活性或毒性无关。超过80%的血浆D - 青霉胺与蛋白质结合，尤其是白蛋白。其余主要以游离还原形式或二硫化物形式存在。只有一小部分剂量在肝脏中代谢为S - 甲基 - D - 青霉胺。消除途径主要是肾脏；二硫化物是尿液中发现的主要化合物。粪便排泄主要对应于药物未吸收的部分。
