DRUG-PROTEIN CONJUGATES .15. A STUDY OF THE DISPOSITION OF D-PENICILLAMINE IN THE RAT AND ITS RELATIONSHIP TO IMMUNOGENICITY
DRUG-PROTEIN CONJUGATES .15. A STUDY OF THE DISPOSITION OF D-PENICILLAMINE IN THE RAT AND ITS RELATIONSHIP TO IMMUNOGENICITY
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DOI：
10.1016/0006-2952(88)90148-7
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发表时间：
1988-02-15
影响因子：
5.8
通讯作者：
PARK, BK
中科院分区：
文献类型：
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作者：
COLEMAN, JW;FOSTER, AL;PARK, BK
用雄性Wistar大鼠在体外和体内研究了[14C] D-青霉胺（PA）的处置。不可逆结合的[14 C] PA分离的大鼠血浆蛋白在体外达到最大的20.6%的总放射性的6小时。不可逆结合的[14 C] PA可以与二硫苏糖醇解离，表明共轭是通过二硫键。大鼠静脉给予[14 C] PA（27 μ mol/kg）后3小时，100%的血浆放射性不可逆结合，约占剂量的3.5%。对PA-血浆蛋白结合物处置的进一步研究表明，在体内容易发生解离：结合物的血浆半衰期约为3小时。游离[14 C] PA是游离和结合药物给药后的主要尿液代谢产物。这些研究表明，PA的处置是类似的结构相关的巯基药物卡托普利（CP）的报告。i.p.和i.m.给予游离PA（340 μ mol/kg和3.4 mmol/kg）。以每月一次的间隔每天给药4天，以及以每月一次的间隔通过单次腹膜内注射给予PA-KLH缀合物（100 μ g/大鼠），有或没有弗氏完全佐剂，都不能诱导通过ELISA可检测的PA特异性IgG或IgM抗体应答。相反，通过与游离PA相同的方案施用的CP（270 μ mol/kg）在第三系列每月注射后诱导CP特异性IgG抗体应答。这些数据表明，PA和CP之间的免疫原性差异源于半抗原内在免疫原性的差异，而不是源于它们的处置。
The disposition of [14C]D-penicillamine (PA) was investigated in vitro and in vivo with male Wistar rats. Irreversible binding of [14C]PA to isolated rat plasma proteins in vitro reached a maximum of 20.6% of total radioactivity of 6 hr. Irreversibly bound [14C]PA could be dissociated with dithiothreitol, demonstrating that conjugation was via disulphide linkage. Three hours after i.v. administration of [14C]PA (27 .mu.mol/kg) to rats 100% of plasma radioactivity was irreversibly bound, representing approximately 3.5% of the dose. Further studies on the disposition of PA-plasma protein conjugates showed that dissociation occurred readily in vivo: the plasma half-life of the conjugate was approximately 3 hr. Free [14C]PA was the major urinary metabolite after administration of both free and conjugated drug. These studies show that the disposition of PA is similar to that reported for the structurally related sulphydryl drug captopril (CP). Free PA (340 .mu.mol/kg and 3.4 mmol/kg) administered i.p. and i.m. daily for 4 days at one monthly intervals, and also PA-KLH conjugate (100 .mu.g/rat) administered by single i.p. injection at monthly intervals with and without Freund''s complete adjuvant, failed to induce PA-specific IgG or IgM antibody responses detectable by ELISA. In contrast, CP (270 .mu.mol/kg), administered by the same protocol as free PA, induced a CP-specific IgG antibody response after the third series of monthly injections. These data suggest that the difference in immunogenicity between PA and CP arises from a difference in the intrinsic immunogenicity of the haptens, rather than from their disposition.