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Valproic acid and active unsaturated metabolite (2‐EN): Transfer to mouse liver following human therapeutic doses
Author(s) -
Nau Heinz,
Loscher Wolfgang
Publication year - 1985
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510060102
Subject(s) - metabolite , valproic acid , chemistry , active metabolite , anticonvulsant , pharmacokinetics , pharmacology , metabolism , toxicity , plasma concentration , biochemistry , biology , epilepsy , organic chemistry , neuroscience
The transfer of valproic acid (VPA, 2‐propylpentanoic acid) and its unsaturated active metabolite (2‐en, 2‐propyl‐2‐pentenoic acid) from plasma to liver has been studied in the mouse between 2 min and 6 h following oral administration of 50 mg of the sodium salts per kg body weight. Transfer of both compounds was extremely rapid. Liver concentrations of VPA were higher than those in plasma, while liver concentrations of 2‐en were lower than those in plasma. The low hepatic levels of 2‐en may be explained by extensive plasma protein binding of this metabolite. The liver/plasma concentration ratios were concentration‐dependent, indicating the presence of active transport mechanisms and/or saturation of plasma protein binding. Our results indicate that 2‐en should be further studied in regard to its potential for the induction of liver toxicity. The desirable low level of 2‐en reached in the liver, seen together with previously observed favourable‐anticonvulsant profile and low teratogenicity, would indicate that this compound may be a valuable alternative antiepileptic agent.