oxadiazoles and Porphyrias

Administration of many antiepileptic drugs to patients with porphyria can precipitate an acute porphyric crisis. Information on the porphyrogenic activity of new antiepileptic drugs is still limited. In the presented study, the effects of tiagabine and topiramate on porphyrin metabolism were evaluated in an in vivo model of porphyria. Administration of the protoporphyrinogen oxidase inhibitor oxadiazon (12.5 mg/kg/day) for four days to male Wistar rats caused a partial block of porphyrin biosynthesis, thus mimicking the condition of quiescent variegate porphyria. Administration of phenobarbital (75 mg/kg/day) to oxadiazon-pretreated rats increased liver porphyrin content, liver porphobilinogen content (means 480 nmol/g, control less than 20 nmol/g) and urinary excretion of porphobilinogen (means 1,000 micromol/l, control less than 20 micromol/l). Tiagabine (75 mg/kg/day) and topiramate (75 mg/kg/day) increased liver porphobilinogen content (means 33 and 53 nmol/g respectively) and urinary porphobilinogen concentration (240 and 490 micromol/l respectively). Similar results were obtained in oxadiazon-treated BALB/c mice. In untreated rats, tiagabine and topiramate caused a moderate increase of hepatic pentoxyresorufin-O-dealkylase activity (approximately 100 and 200 pmol/min./mg respectively, controls 15 pmol/min./mg). These data demonstrate that administration of tiagabine or topiramate to oxadiazon-treated animals can provoke a condition resembling an acute porphyric attack and suggest that administration of these drugs to patients with suspected porphyria should be avoided. However, 5-day administration of both tiagabine and topiramate (75 mg/kg) is considerably less porphyrogenic than phenobarbital administered at the same dose.

Topics: Animals; Anticonvulsants; Drug Interactions; Fructose; Herbicides; Kidney; Liver; Male; Mice; Mice, Inbred BALB C; Nipecotic Acids; Oxadiazoles; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Phenobarbital; Porphyrias; Porphyrins; Protoporphyrinogen Oxidase; Rats; Rats, Wistar; Tiagabine; Topiramate

Administration of 3-[2-(2,4,6-trimethylphenyl)-thioethyl]-4-methylsydnone (TTMS) induces hepatic porphyria in rats, mice and dogs. The protoporphyrin pigment in livers of rats and mice is found mainly in bile ducts and leads to bile duct proliferation and portal inflammation. Dog livers contain protoporphyrin predominantly in bile canaliculi. The birefringence of the pigment appears to be associated with bilamellar components within the pigment. The markedly depressed catalase activity in livers of rats does not increase after clofibrate administration. The catalase activity of mouse liver is depressed slightly and responds to clofibrate treatment.

Topics: Alcohol Oxidoreductases; Animals; Bile Ducts, Intrahepatic; Body Weight; Catalase; Chemical and Drug Induced Liver Injury; Clofibrate; D-Amino-Acid Oxidase; Disease Models, Animal; Dogs; Female; Glycolates; Kidney; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Organ Size; Oxadiazoles; Porphyrias; Porphyrins; Rats; Species Specificity; Spleen; Sydnones; Urate Oxidase