The toxicity of tetrahydrobiopterin: acute and subchronic studies in mice.
Tetrahydrobiopterin (BH4) is presently being employed in clinical trials for the therapy of various neurological disorders. The toxicity of BH4 in mice was analyzed by acute and subchronic intraperitoneal and acute oral survival studies. Organ weight analysis and histopathology were performed after acute and subchronic i.p. administration. The effect of probenecid on BH4 toxicity was also tested. An LD50 of approximately 260 mg/kg was obtained from acute (14-day) intraperitoneal survival studies. A dose-dependent increase in kidney weights and histopathologic evidence of acute toxic tubular necrosis were noted in acute i.p. studies. Acute oral administration of up to 1318 mg/kg BH4 did not cause any significant morbidity or mortality, nor did subchronic (92-day) i.p. administration of 10 or 50 mg/kg BH4. Probenecid pretreatment did not decrease the toxicity of BH4. The importance of further evaluation of the potential toxicity of tetrahydrobiopterin in clinical utilization is emphasized.
D000284:Administration, Oral; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D005260:Female; D007274:Injections, Intraperitoneal; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000473:pathology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011339:Probenecid / Q000494:pharmacology; D013997:Time Factors
D001708:Biopterins; C003402:sapropterin; D011339:Probenecid