title: Paracetamol prevents hyperglycinemia in vervet monkeys treated with valproate.
abstract: Valproate administration increases the level of the inhibitory transmitter, glycine, in the urine and plasma of patients and experimental animals. Nonketotic hyperglycinemia (NKH), an autosomal recessive disorder of glycine metabolism, causes increased glycine concentrations in blood, urine, and cerebrospinal fluid (CSF), most likely due to a defect in the glycine cleavage enzyme or possibly deficits in glycine transport across cell membranes. We investigated the relationship between the hyperglycinemic effect of valproate and induced pyroglutamic aciduria via paracetamol in the vervet monkey. Firstly it was determined if valproate could induce hyperglycinemia in the monkey. The second aim was to increase glutamic acid (oxoproline) urine excretion using paracetamol as a pre-treatment and to assess whether valproate has an influence on the γ-glutamyl cycle. Hyperglycinemia was induced in healthy vervet monkeys when treated with a single oral dose of 50 mg/kg valproate. An acute dose of 50 mg/kg paracetamol increased oxoproline in the urine. Pre-treatment with paracetamol opposed the hyperglycinemic effect of valproate. However, the CSF:serum glycine ratio in a nonketotic monkey increased markedly after paracetamol treatment and remained high following valproate treatment. These results indicate that the γ-glutamyl cycle does indeed play a role in the hyperglycinemic effect of valproate treatment, and that paracetamol may have value in preventing and/or treating valproate-induced NKH.
authors.affiliation: Pharmaceutical Chemistry, Unit for Drug Research and Development, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Jacques
authors.initials: J
authors.lastname: Viljoen
authors.forename: Jakobus J
authors.initials: JJ
authors.lastname: Bergh
authors.forename: Lodewyk J
authors.initials: LJ
authors.lastname: Mienie
authors.forename: Hercullas F
authors.initials: HF
authors.lastname: Kotze
authors.forename: Gisella
authors.initials: G
authors.lastname: Terre'Blanche
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology* / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D005998:Glycine / Q000097:blood / Q000652:urine; D020158:Hyperglycinemia, Nonketotic / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D010865:Pilot Projects; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D018712:Analgesics, Non-Narcotic; D000927:Anticonvulsants; D000082:Acetaminophen; D014635:Valproic Acid; D005998:Glycine