title: Studies on pharmacokinetic mechanism of phenytoin resistance in refractory epilepsy.
abstract: P-glycoprotein (P-gp) is a drug efflux pump in many organs, including the intestine and liver. Two single nucleotide polymorphisms (SNPs) of P-gp gene, 2677G>T and 3435C>T, were reported to influence function and expression of P-gp and have the controversial effects on drug disposition. Phenytoin is one substrate of P-gp. Persistent low phenytoin levels in plasma and P-gp overexpression in brain in several refractory epilepsy patients were reported. P-gp polymorphisms may also affect phenytoin efficacy by altering its bioavailability (F). Because two P-gp SNPs, 2677G>T and 3435C>T, may affect P-gp expression in tissue, we examined phenytoin disposition in patients of different P-gp haplotypes, G/G2677C/C3435 and T/T2677T/T3435. We found that the mean absolute F of phenytoin in T/T2677T/T3435 subjects (91%) is slightly higher than in G/G2677C/C3435 subjects (82%). There was no difference in the maximum concentration (Cmax ) and the area under the serum concentration-time curve of phenytoin administered orally between two genotypic groups. However, the time of maximum concentration was higher in T/T2677T/T3435 subjects (10 h) than in G/G2677C/C3435 subjects (6 h). The study ruled out the possibility that genetic polymorphisms of P-gp may affect phenytoin efficacy through the decreased absorption or the increased elimination. P-gp SNPs could affect phenytoin efficacy in refractory epilepsy patients probably because of central nervous system.
authors: Department of Neurology, National Cheng Kung University, Medical College, Tainan, Taiwan.
authors: Ming-Liang
authors: ML
authors: Lai
authors: Yu-En
authors: YE
authors: Tien
authors: Ying-Syuan
authors: YS
authors: Huang
authors: Jin-Ding
authors: JD
authors: Huang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood*; D001682:Biological Availability; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy*; D005838:Genotype; D006801:Humans; D008297:Male; D010672:Phenytoin / Q000008:administration & dosage / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D010672:Phenytoin
keywords: P-glycoprotein; absorption; bioavailability; disposition; drug transport; efflux pumps; genetic polymorphisms; haplotype; high-performance/pressure liquid chromatography (HPLC); pharamcokinetics