Abstract
Metabolism and renal excretion of valproic acid (VPA) were examined in maternal, fetal, and newborn sheep to identify the underlying reasons for the previously observed reduced VPA clearance in newborn lambs. Plasma and urine from VPA infusion studies in maternal, fetal, and newborn sheep were analyzed for VPA and its metabolites [VPA-glucuronide; β-oxidation products: (E)-2-ene, (E)-3-ene, and 3-keto VPA; hydroxylated metabolites: 3-hydroxy, 4-hydroxy, and 5-hydroxy VPA (5-OH VPA); and 4-ene VPA, 4-keto VPA, 2-propylglutaric acid, and 2-propylsuccinic acid] using gas chromatography-mass spectrometry. All measured metabolites were detectable in maternal and fetal plasma, with 3-keto and 5-OH VPA being at higher concentrations in the fetus. Plasma concentrations of (E)-2-ene, (E)-3-ene, 3-keto, and 5-OH VPA were higher in the newborn compared with the mother, whereas those of the other metabolites were similar. A smaller percentage of the dose was excreted as VPA-glucuronide in newborn lamb urine (28.3 ± 12.0%) compared with the mother (77.0 ± 7.8%). Similarly, a lower fraction of the dose was excreted unchanged in newborn urine (11.0 ± 5.8%) relative to the urine of the mother (19.3 ± 5.8%); however, significantly larger percentages were excreted as (E)-2-ene (0.11 ± 0.04 versus 0.02 ± 0.01%), 3-keto (11.6 ± 3.5 versus 1.6 ± 0.8%), 4-hydroxy (6.1 ± 3.2 versus 2.3 ± 1.3%), and 5-OH VPA (2.2 ± 0.6 versus. 0.8 ± 0.6%). The major reason for the reduced VPA elimination in newborn lambs appears to be impaired renal excretion and glucuronidation capacity. As a result, a larger fraction of the dose is channeled to β-oxidation and hydroxylation pathways. The β-oxidation activities are high at birth; this may explain the high plasma concentrations of (E)-2-ene and 3-keto VPA observed in newborn lambs and human newborns exposed to VPA.
Footnotes
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Send reprint requests to: Dr. Dan W. Rurak, B.C. Research Institute for Children's and Women's Health, 950 West 28th Ave., Vancouver, British Columbia, Canada V5Z 4H4. E-mail:drurak{at}cw.bc.ca
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↵1 A part of this work was presented at the 5th International Meeting of the International Society for the Study of Xenobiotics (1998) and is abstracted in ISSX Proc13:74, 1998.
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These studies were supported by funding from the Medical Research Council of Canada. S.K. was the recipient of a University of British Columbia Graduate Fellowship. H.W. is supported by a Pharmaceutical Manufacturers Association of Canada/Medical Research Council of Canada studentship. D.W.R. is the recipient of an Investigatorship award from the British Columbia Children's Hospital Foundation.
- Abbreviations used are::
- VPA
- valproic acid
- Cmax
- maximal plasma concentration
- LOQ
- lower limit of quantification
- 3-OH VPA
- 2-n-propyl-3-hydroxy pentanoic acid
- 4-OH VPA
- 2-n-propyl-4-hydroxy pentanoic acid
- 5-OH VPA
- 2-n-propyl-5-hydroxy pentanoic acid
- 2-PSA
- 2-propylsuccinic acid
- 2-PGA
- 2-propylglutaric acid
- 2-ene VPA
- 2-n-propyl-2-pentenoic acid
- 3-ene VPA
- 2-n-propyl-3-pentenoic acid
- 3-keto VPA
- 2-n-propyl-3-oxopentanoic acid
- 4-keto VPA
- 2-n-propyl-4-oxopentanoic acid
- 4-ene VPA
- 2-n-propyl-4-pentenoic acid
- Received September 2, 1999.
- Accepted February 16, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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