Metabolism of pantethine in cystinosis.
Metabolism of pantethine in cystinosis.
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胱氨酸病中泛硫氨酸的代谢。
DOI：
10.1172/jci112152
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发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Thoene,JG
中科院分区：
文献类型：
--
作者：
Wittwer,CT;Gahl,WA;Butler,JD;Zatz,M;Thoene,JG
D-泛硫乙胺是维生素泛酸和低分子量氨基硫醇半胱胺的缀合物。泛硫乙胺是一种实验性降血脂剂，已被建议作为治疗肾病性胱氨酸病的半胱胺来源。我们用70- 1，000 mg/kg/d口服D-泛硫乙胺治疗4名胱氨酸病儿童，并研究其代谢。泛硫乙胺迅速水解为泛酸和半胱胺;口服给药后，我们无法在血浆中检测到泛硫乙胺。负责的酶，“泛酰巯基乙胺酶”，是高度活跃的小肠粘膜和血浆匀浆。大鼠肠道酶的米氏常数为4.6 μ M，其pH值曲线显示在4和9之间的宽平台。口服泛硫乙胺后的泛酸盐药代动力学遵循开放的二室模型，维生素消除缓慢（t1/2 = 28 h）。峰值血浆泛酸发生在2.5小时，超过250 μ M的水平被认为是正常的300倍。泛酸的表观全身储存是显著的（25 mg/kg），并且在泛硫乙胺治疗后数月血浆水平升高了三倍。泛硫乙胺后的血浆半胱胺浓度类似于等效剂量的半胱胺后报道的那些。然而，最多仅发生80%的白色血细胞胱氨酸消耗。我们的结论是泛硫乙胺可能是治疗肾病性胱氨酸病的有效性低于半胱胺，应该只考虑在半胱胺不耐受的情况下。血清胆固醇平均降低14%，这支持泛硫乙胺作为降血脂剂的潜在临床意义。泛硫乙胺在体内的快速水解表明泛酸或半胱胺可能是其降血脂作用的效应物。
D-Pantethine is a conjugate of the vitamin pantothenic acid and the low-molecular-weight aminothiol cysteamine. Pantethine is an experimental hypolipemic agent and has been suggested as a source of cysteamine in the treatment of nephropathic cystinosis. We treated four cystinotic children with 70-1,000 mg/kg per d oral D-pantethine and studied its metabolism. Pantethine was rapidly hydrolyzed to pantothenic acid and cysteamine; we could not detect pantethine in plasma after oral administration. The responsible enzyme, "pantetheinase," was highly active in homogenates of small intestinal mucosa and plasma. The Michaelis constant of the rat intestinal enzyme was 4.6 microM and its pH profile showed a broad plateau between 4 and 9. Pantothenate pharmacokinetics after orally administered pantethine followed an open two-compartment model with slow vitamin elimination (t1/2 = 28 h). Peak plasma pantothenate occurred at 2.5 h and levels over 250 microM were seen at 300 times normal. Apparent total body storage of pantothenate was significant (25 mg/kg), and plasma levels were elevated threefold for months after pantethine therapy. Plasma cysteamine concentrations after pantethine were similar to those reported after equivalent doses of cysteamine. However, at best only 80% white blood cell cystine depletion occurred. We conclude that pantethine is probably less effective than cysteamine in the treatment of nephropathic cystinosis and should only be considered in cases of cysteamine intolerance. Serum cholesterol was decreased an average of 14%, which supports the potential clinical significance of pantethine as a hypolipemic agent. Rapid in vivo hydrolysis of pantethine suggests that pantothenate or cysteamine may be the effectors of its hypolipemic action.