Stability of thalidomide in human plasma.

Stability of Thalidomide in Human Plasma To the Editor: Thalidomide was initially introduced into medical use in the 1950s as a sedative; because of its terato-genie effects (malformation of the extremities), however, it was withdrawn from the market. Chronic use of thalidomide was also associated with peripheral neuritis. Lately, interest in thalidomide has renewed after demonstration of its activity in various inflammatory and autoini-mune disorders, including oropharyn-geal ulcerations, Behcet syndrome, lepra reactions, and graft-vs-host disease a4)kr bone marrow transplanta-tion (1 2). The mechanism of action of thalidomide in these diseases is not known. Only limited information is available on the pharmacokinetics of the drug and its optimum dosage in these new potential indications. Especially when used in severely ifi patients with advanced changes of the gastrointestinal function, e.g., the treatment of complicated forms of graft-vs-host-disease after bone marrow transplantation, the absorption of thalidomide may be unpredictable. According to animal studies, a minimal plasma thalidomide concentration of 5 mg/L is necessary to produce a maximal response (3). To improve the efficacy and safety of thalidomide therapy in humans will require further studies in target patient populations. Thalidomide is almost insoluble in water and only fairly soluble in most organic solvents. In aqueous solutions , it undergoes spontaneous hy-drolysis at physiological and alkaline pH (4). Hydrolysis of thalidomide has also been noted in plasma of several animal species, including monkeys, such that only-80% of the added drug is found unchanged after 60 min incubation at 37 #{176}C (5). However, the occurrence of hydrolysis in human plasma has been questioned; in an earlier study, no statistically significant change in plasma thalidomide concentration was noted in samples stored for 1 h at room temperature (6). We evaluated the stability of tha-lidomide in human plasma and the specifity and reproducibility of its determination by using the HPLC method of Chen et al. (6). A Merck-Hitachi L6200 pump apparatus (Hi-tachi, Tokyo, Japan) was used with a LiChroCART 100 RP-8 column (250 X 4 mm) and precolumn (4 x 4 mm; E. Merck, Darmstadt, Germany). The mobile phase was set up from eluent A (methanol:potassium phosphate, 0.01 mmol/L, pH 6.2, 10:90, by vol) and eluent B (methanol), going from 20% to 80% eluent B over 12 min. All reagents were of analytical grade (E. Merck). The flow rate was 1.5 mL/ miii. The intraassay CV of plasma thalidomide determinations was 6.7% at 1.5 mgfL and 1.5% at …