ELEVATION OF WHOLE-BLOOD GLUTATHIONE IN PERITONEAL-DIALYSIS PATIENTS BY L-2-OXOTHIAZOLIDINE-4-CARBOXYLATE, A CYSTEINE PRODRUG (PROCYSTEINE(R))

Glutathione is a major cellular antioxidant that protects protein thio ls and inhibits cellular damage due to oxygen free radicals. It has be en reported previously that patients undergoing dialysis have low leve ls of blood glutathione, which may lead to increased susceptibility to oxidant stress. L-2-oxothiazolidine-4-carboxylic acid (OTZ) is a cyst eine prodrug that raises cellular glutathione levels by increasing del ivery of cysteine, the rate-limiting substrate for glutathione syn the sis. This study investigates the effect of OTZ on blood glutathione in a blinded, placebo-controlled study of patients with chronic renal fa ilure treated by peritoneal dialysis. Twenty patients were randomly se lected to receive OTZ (0.5 g three times a day orally with meals) or p lacebo for 14 d. Patients visited the clinic for predose blood collect ion and safety evaluation at baseline (days 3, 7, and 14 and again at 14 d from the last dose [follow-up]). Glutathione concentrations were determined in whole blood by HPLC. OTZ resulted in a significant rise in whole-blood glutathione at days 7 (594 +/- 129 mu mol/L) and 14 (62 0 +/- 108 mu mol/L) compared with baseline (544 +/- 139 mu mol/L) (P < 0.01 and P < 0.05, respectively). Glutathione was also significantly increased at days 7 and 14 when normalized by hematocrit (Hct) or hemo globin to correct for anemic status (e.g., 20.7 +/- 5.7 mu mol/L per % Hct [day 7] and 20.9 +/- 4.0 mu mol/L per % Hct [day 14] versus 18.0 +/- 4.2 mu mol/L per % Hct [baseline]; P < 0.05). Glutathione levels d id not change in the placebo group at any patient visit, and levels in the OTZ-treated group returned to baseline at follow-up. There were n o serious adverse events attributable to OTZ, and the drug appeared to be well tolerated by patients with renal failure treated by continuou s ambulatory peritoneal dialysis. Our results show that OTZ increases blood glutathione levels, which may improve antioxidant status in dial ysis patients.