876 METABOLISM OF PANTETHINE IN NEPHROPATHIC CYSTINOSIS

Abstract

Previous in vitro studies with cystinotic fibroblasts have shown D-pantethine to be as effective as cysteamine in decreasing intracellular cystine. We studied the in vivo metabolism and efficacy of oral pantethine (70-1000 mg/kg/day) in three cystinotic children. WBC cystine, plasma cysteamine, plasma and urinary pantothenate, and total urinary sulfur were measured. No pantethine was detected in plasma or urine, but plasma pantothenate was elevated to over 200 times normal. After a single 60 mg/kg dose, an open two compartment model gave rate constants of 0.025/hr for elimination and 1.2/hr for distribution of pantothenate. At optimal pantethine doses, plasma cysteamine levels (ca. 50 nmol/ml) were comparable to those after cysteamine treatment. However, maximal WBC cystine depletion on pantethine was only 60-80%, whereas cysteamine produces over 90% depletion. Pantethine absorption was estimated by pantothenate and sulfur excretion. Only 3-12% of the dose was excreted as pantothenate. At 250 mg/kg/day, ca. 50% of the administered sulfur was excreted. At higher doses, no significant increase in sulfur excretion occurred. An osmotic diarrhea occurred at doses above 350mg/kg/day. Pantethine, pantothenate, and cysteamine were the major osmotic agents. Excess pantethine (10-fold over pantetheine) inhibited pantetheinase from an intestinal biopsy by 30%. Dosing t.i.d. with meals vs q6h increased adsorption and WBC cystine depletion at 250 mg/kg/day. Limited intestinal hydrolysis and absorption of pantethine limit its usefulness in cystinosis.

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