[Effects of phenobarbital on the metabolism of ACNU in vivo].
The nitrosourea compounds are often used in the treatment of patients with malignant brain tumors in combination with anticonvulsants, such as phenobarbital (PB). Since PB can induce hepatic microsomal enzyme--P 450 and degrade nitrosoureas in vivo, the effect of PB on tumoricidal activity in relation to toxicity of 3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) was studied using a rat brain tumor model. To determine toxicity, CD-Fisher rats were treated for 4 days with 19 and 38 mg/kg/day of PB (i.m), 0.4 and 0.7 g/kg/day of sodium valproate--SV (p.o), or 3 days with 50 mg/kg of phenytoin (i.v) prior to an administration of 47 mg/kg of ACNU (i.p). The mortality rate by the toxicity within 14 days after administration of ACNU was calculated in each group. The toxicity of ACNU was markedly reduced in PB pretreated rats compared with those without pretreatment or treated with SV or phenytoin. The tumoricidal activity of ACNU was evaluated in CD-Fisher rats with RG 12 brain tumors. Rats received 20 mg/kg ACNU after pretreatment with 19 mg/kg/day of PB (i.m) or 0.2 g/kg/day of SV (p.o) for 4 days. The mean survival days and the percentage increase in life span (%ILS) were compared in each group. Pretreatment with PB significantly reduced the tumoricidal activity of ACNU as compared with control without pretreatment (p less than 0.001) or pretreatment with SV (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy; D005910:Glioma / Q000188:drug therapy; D008297:Male; D015376:Nimustine; D009607:Nitrosourea Compounds / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D015376:Nimustine; D010634:Phenobarbital