Abstract
An earlier study in rats revealed that α-fluorination of 2-propyl-4-pentenoic acid (4-ene VPA), a toxic metabolite of the anticonvulsant drug valproic acid, would avert its metabolismvia β-oxidation and eliminate the drug-related hepatotoxicity. This investigation was carried out to compare 4-ene VPA and the α-fluorinated analogue (α-fluoro-4-ene VPA) for their pharmacokinetic and protein binding properties. Male Sprague-Dawley rats were dosed with either 4-ene VPA or α-fluoro-4-ene VPA ip at 1.4 mmol/kg. Blood was collected from the tail vein at various time points and serum samples were prepared. Urine was collected for 24 hr. A second set of rats was treated the same but sacrificed 1 hr post dose, and the livers were homogenized in a Tris-buffer. Protein binding was assessed via ultrafiltration of the naive serum samples spiked with either of the drugs. The serum drug concentration-time profiles of 4-ene VPA and α-fluoro-4-ene VPA seemed to resemble one another during the initial 200 min within which differences were reported for their effects on mitochondrial GSH. A second serum peak concentration was observed for 4-ene VPA at ∼300 min, which was attributed to the extensive glucuronidation of the drug and enterohepatic circulation. The α-fluoro-4-ene VPA, on the other hand, did not show these properties with its major phase II metabolite being the corresponding L-glutamine conjugate. The toxic metabolite (E)-2-propyl-2,4-pentadienoic acid and its N-acetylcysteine conjugate were detected only in 4-ene VPA treated rats. Liver concentrations of 4-ene VPA and α-fluoro-4-ene VPA were 0.96 ± 0.11 and 0.89 ± 0.19 μmol/g of wet liver, respectively, at 1 hr after the dose. Comparable and parallel serum free drug levels were apparent for the two drugs over a concentration range of 0.25 to 2.9 μmol/ml. Taken together, the data seem to suggest that the reported distinction in the ability of 4-ene VPA and α-fluoro-4-ene VPA to produce liver toxicity in the rat resides in differences in their metabolism rather than in their pharmacokinetic properties.
Footnotes
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Send reprint requests to: Dr. Frank S. Abbott, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C., Canada, V6T 1Z3.
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2 Preliminary accounts of these studies were presented at the fifth North American ISSX Meeting, Tucson, AZ, October 1993 and the ninth annual meeting of the American Association of Pharmaceutical Scientists, San Diego, CA, November 1994.
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3 This research was supported by a program grant from the Medical Research Council of Canada.
- Abbreviations used are::
- CoA
- co-enzyme A
- (E)-2
- 4-diene VPA, (E)-2-propyl-2,4-pentadienoic acid
- 4-ene VPA
- 2-propyl-4-pentenoic acid
- GSH
- glutathione
- α-fluoro-4-ene VPA
- 2-fluoro-2-propyl-4-pentenoic acid
- α-fluoro-4-ene VPA-Gln
- N2-(2-fluoro-2-propyl-4-pentenoyl)glutamine
- 3-keto-4-ene VPA
- 2-propyl-3-oxo-4-pentenoic acid
- NAC
- N-acetyl-L-cysteine
- 5-NAC-3-ene VPA
- 2-propyl-5-(N-acetylcystein-S-yl)-3-pentenoic acid
- 5-NAC-2-fluoro-4-hydroxy VPA-lactone
- 2-propyl-2-fluoro-5-(N-acetylcystein-S-yl)-4-hydroxypentanoic acid lactone
- 5-NAC-4-hydroxy VPA-lactone
- 2-propyl-5-(N-acetylcystein-S-yl)-4-hydroxylpentanoic acid lactone
- P-450
- cytochrome P-450
- TFA
- trifluoroacetic acid
- VPA
- valproic acid, 2-propylpentanoic acid
- CID
- collision-induced dissociation
- EI
- electron impact ionization
- LC/MS/MS
- combined liquid chromatography/tandem mass spectrometry
- MRM
- multiple reaction monitoring
- SIM
- single ion monitoring
- Received July 31, 1996.
- Accepted November 8, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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