title: Alterations in the renal excretion of valproate and its metabolites after chronic treatment.
abstract: Urinary excretion of valproate (VPA, administered as its sodium salt) and its various metabolites was studied in rats before and after 6 weeks of chronic treatment with intraperitoneal (i.p.) injection of 200 mg/kg VPA three times daily. Urinary excretion was determined after i.p. injection of a single dose of 200 mg/kg VPA, to which [14C]labeled VPA had been added to yield a dose of 1 microCi/kg body weight. Unlabeled VPA and metabolites were determined in urine by gas chromatography-mass spectrometry (GC-MS). After injection of a single dose of VPA before onset of chronic treatment, approximately 40-50% of the dose administered was excreted in the urine within 24 h, mainly in the form of conjugated VPA and omega-oxidation products, i.e., 5-hydroxy-VPA and 2-propyl-glutaric acid. After chronic treatment, urinary excretion of total radioactivity increased approximately 75% as compared with activity before chronic treatment, demonstrating a marked increase in elimination rate of VPA during prolonged administration. Determination of VPA and metabolites in urine by GC-MS indicated that this enhanced elimination resulted mainly from increases in glucuronidation and beta-oxidation of VPA, whereas omega-oxidation was apparently not altered or was even reduced. The data strongly indicate that at least in rats VPA produces induction of its own metabolism during prolonged treatment.
authors.affiliation: Institute of Toxicology and Embryopharmacology, Free University of Berlin, F.R.G.
authors.forename: J E
authors.initials: JE
authors.lastname: Fisher
authors.forename: H
authors.initials: H
authors.lastname: Nau
authors.forename: W
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000818:Animals; D001192:Arylsulfatases / Q000378:metabolism; D001711:Biotransformation; D002250:Carbon Radioisotopes; D004790:Enzyme Induction; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005966:Glucuronidase / Q000378:metabolism; D007274:Injections, Intraperitoneal; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000652:urine*
chemical_list: D002250:Carbon Radioisotopes; D014635:Valproic Acid; D001192:Arylsulfatases; D005966:Glucuronidase