Trimethoprim potentiates valproic acid-induced neural tube defects (NTDs) in mice.
The antiepileptic drug valproic acid (VPA) may produce NTDs because of interference with folate metabolism. Therefore, the possible interactions of VPA with the dihydrofolate reductase inhibitor trimethoprim (TM) was investigated. The combination of TM with sulfamethoxazol is used for treatment of urinary infections, the most common complications of pregnancy. TM (80 and 160 mg/kg) was given i.p. and orally, 0.5 and 1 h, respectively, prior to valproic acid (VPA, 300 and 400 mg/kg, s.c.) in day 8 pregnant NMRI mice. Fetuses were examined for exencephaly, resorptions, and fetal weight retardation on day 18 of gestation. TM (160 mg/kg, i.p.) produced no exencephaly or embryolethality, but increased fetal weight. Administration of TM (80 mg/kg, i.p.) increased VPA-induced exencephaly and fetal weight retardation but not embryolethality. Exencephaly rates induced by VPA (300 and 400 mg/kg) were 4% and 12.9% and were increased by coadministration of TM to 22.7% and 42.5%, respectively (P < 0.01). Oral TM also increased VPA-induced exencephaly and fetal weight retardation but with lower potency than i.p. injection. The observed effects were not due to altered VPA pharmacokinetics. These results support the view that VPA-induced neural tube defects may be mediated via an interaction with folate metabolism, and advise against TM-use in VPA-treated epileptics during pregnancy.
Elmazar
M M
MM
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Egypt.
Nau
H
H
D000818:Animals; D004357:Drug Synergism; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005493:Folic Acid Antagonists; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009436:Neural Tube Defects / Q000139:chemically induced*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000139:chemically induced; D014295:Trimethoprim / Q000633:toxicity*; D014635:Valproic Acid / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*
D005493:Folic Acid Antagonists; D014635:Valproic Acid; D005492:Folic Acid; D014295:Trimethoprim