TOXICITY EVALUATIONS OF L-CYSTEINE AND PROCYSTEINE(TM), A CYSTEINE PRODRUG, GIVEN ONCE INTRAVENOUSLY TO NEONATAL RATS

Decreased enzymatic production of cysteine in premature and newborn in fants may limit the synthesis of glutathione. Unfortunately, cysteine supplementation is limited by associated toxicity and product instabil ity. Procysteine(TM) (L-2-oxothiazolidine-4-carboxylate) is a prodrug of cysteine that is inert until metabolized to cysteine intracellulary , thus stimulating glutathione synthesis. The potential toxicities of cysteine and Procysteine(TM) were compared in two studies with neonata l rats (10 per group; 3 +/- 1 days of age) after a single intravenous administration. In one study, acute high dosage survivorship was compa red for approximately equimolar cysteine dosages Of L-cysteine and Pro cysteine(TM). Mortality at 7 days after single intravenous dosages Of L-cysteine at 1.52 or 1.14 g/kg or Procysteine(TM) at 1.80 or 1.35 g/k g was 80, 50, 10 and 0%, respectively. Clinical pathology parameters a nd body and organ weights were compared in a second study, following a moderate dosage of Procysteine(TM) or equimolar or lower dosages Of L -cysteine. No differences were observed in clinical pathology paramete rs nor body or organ weights at 14 days following single intravenous d osages Of L-cysteine at 369, 185 or 37 mg/kg or Procysteine(TM) at 450 mg/kg. Also, Procysteine(TM) solutions were considerably more stable than L-cysteine solutions (months vs. hours, respectively). These stud ies indicated that cysteine supplementation in infants may be enhanced by Procysteine(TM) administration.