Drug Interaction between Phenytoin and Allopurinol

• Published in: Journal of Pharmacobio-Dynamics Vol. 13; no. 1; pp. 36 - 43
• Main Authors: OGISO, Taro, ITO, Yoshimasa, IWAKI, Masahiro, TSUNEKAWA, Ken
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1990; Pharmaceutical Society of Japan
• Subjects: Administration, Oral; Allopurinol - pharmacology; Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Kidney - blood supply; Liver - enzymology; Liver - metabolism; Male; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; phenytoin; Phenytoin - administration & dosage; Phenytoin - analogs & derivatives; Phenytoin - metabolism; Phenytoin - pharmacokinetics; Phenytoin - pharmacology; Phenytoin - urine; Rats; Rats, Inbred Strains; Regional Blood Flow - drug effects; Rat; Digestive system; Metabolite; Liver; Rodentia; Oral administration; Enzyme inhibitor; Anticonvulsant; Metabolism; Vertebrata; Mammalia; Animal; Xanthine oxidase; Drug interaction; Mechanism of action; Pharmacokinetics
• ISSN: 0386-846X; 1881-1353
• DOI: 10.1248/bpb1978.13.36

The combination of phenytoin (DPH) and allopurinol is used for the treatment of a neurological disease. However, interactions between DHP and allopurinol and the mechanism are little known. The repeated dosing of allopurinol at higher doses (20 and 50 mg/kg) significantly retarded the elimination of DPH from the circulation and dramatically decreased the urinary excretion of p-hydroxyphenytoin (HPPH), a major metabolite of DPH. However, a single administration of allopurinol (10 or 50 mg/kg) did not give rise to these effects. Allopurinol did not affect the hepatic extraction of DPH and renal plasma flow rate. Allopurinol (50 mg/kg/d) dosed repeatedly could not inhibit the hepatic drug metabolizing enzyme activities. The in vitro hydroxylation of DPH was inhibited only slightly and the kinetic plots gave apparently non-competitive inhibition. The less inhibitory effect of allopurinol on the in vitro hydroxylation did not agree with the in vivo data. These results indicate that the inhibitory effect of allopurinol is not mediated by cytochrome P-450 dependent monooxygenase reactions.