Gopaul V S, Tang W, Farrell K, Abbott F S
Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Drug Metab Dispos. 2003 Jan;31(1):114-21. doi: 10.1124/dmd.31.1.114.
In this study, spectroscopic and chromatographic evidence is presented for the identification and characterization of the metabolites, valproyl glutamate (2-propylpentanoyl glutamate, VPA-GLU) and valproyl glutamine (2-propylpentanoyl glutamine, VPA-GLN) in the urine, serum, and cerebrospinal fluid (CSF) of patients on valproic acid (VPA) therapy. Moreover, the identification of valproyl glycine (2-propylpentanoyl glycine, VPA-GLY) in the serum and urine of patients on VPA, albeit in trace concentrations, is also reported here. The three amino acid conjugates excreted in urine accounted for about 1% of the VPA dose in four patients who were on VPA therapy chronically and had reached steady state. VPA-GLU was quantitatively the most prominent metabolite (0.66-13.1 microg/mg creatinine) compared with VPA-GLN (0.78-9.93 microg/mg creatinine) and VPA-GLY (trace-1.0 microg/mg creatinine) in overnight urine samples of all patients studied (n = 29). The relatively low serum concentrations of the three amino acid conjugates of VPA in six patients suggest that the metabolites are readily excreted once formed. In contrast, whereas VPA GLY was absent in the CSF of one patient on VPA, the concentrations of VPA-GLU and VPA-GLN in this CSF sample were 9 and 5 times, respectively, their corresponding serum concentrations.
在本研究中，提供了光谱和色谱证据，用于鉴定和表征接受丙戊酸（VPA）治疗患者的尿液、血清和脑脊液（CSF）中的代谢产物丙戊酰谷氨酸（2-丙基戊酰谷氨酸，VPA-GLU）和丙戊酰谷氨酰胺（2-丙基戊酰谷氨酰胺，VPA-GLN）。此外，本文还报告了在接受VPA治疗患者的血清和尿液中鉴定出丙戊酰甘氨酸（2-丙基戊酰甘氨酸，VPA-GLY），尽管其浓度很低。在长期接受VPA治疗且已达到稳态的4例患者中，尿液中排泄的这三种氨基酸结合物约占VPA剂量的1%。在所有研究患者（n = 29）的过夜尿液样本中，与VPA-GLN（0.78 - 9.93微克/毫克肌酐）和VPA-GLY（痕量 - 1.0微克/毫克肌酐）相比，VPA-GLU在定量上是最主要的代谢产物（0.66 - 13.1微克/毫克肌酐）。6例患者中VPA的三种氨基酸结合物的血清浓度相对较低，这表明这些代谢产物一旦形成就很容易被排泄。相比之下，在1例接受VPA治疗患者的脑脊液中未检测到VPA-GLY，而该脑脊液样本中VPA-GLU和VPA-GLN的浓度分别是其相应血清浓度的9倍和5倍。
