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Multidrug resistance 1 genotype and disposition of budesonide in early primary biliary cirrhosis
Author(s) -
Dilger Karin,
Cascorbi Ingolf,
Grünhage Frank,
Hohenester Simon,
Sauerbruch Tilman,
Beuers Ulrich
Publication year - 2006
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2005.01222.x
Subject(s) - budesonide , p glycoprotein , primary biliary cirrhosis , cyp3a , genotype , medicine , pharmacology , gastroenterology , disposition , biology , endocrinology , cytochrome p450 , multiple drug resistance , gene , corticosteroid , drug resistance , genetics , metabolism , social psychology , psychology
Background: Budesonide, which is a dual substrate of P‐glycoprotein, the product of the multidrug resistance 1 (MDR1) gene, and cytochrome P450 3A (CYP3A) has been proposed for treatment of early primary biliary cirrhosis (PBC). Recently, MDR1 gene polymorphisms have been discussed as a potential cause of glucocorticoid resistance. We tested the hypothesis that MDR1 gene polymorphisms affect absorption of oral budesonide. Methods: In 21 patients with histologically proven early‐stage (I/II) PBC and nine healthy subjects, we evaluated the impact of MDR1 single nucleotide polymorphisms (2677G>T,A and 3435C>T) on disposition of a single oral dose of 3 mg budesonide. CYP3A5 gene polymorphisms (6986A>G) were analyzed in parallel. Results: In MDR1 2677 GG and 3435 CC genotypes, absorption and elimination of budesonide were not significantly different from those in corresponding homozygous variants. Peak plasma levels and areas under the plasma concentration time curves (AUC) of budesonide were not lower in MDR1 3435 CC with putatively high intestinal expression of P‐glycoprotein than in MDR1 3435 TT. Interestingly, in two CYP3A5 * 1/ * 3 carriers with high enzyme activity, lower AUC was noted than in 28 CYP3A5 * 3/ * 3 carriers with a deficient enzyme. Conclusion: Common MDR1 gene polymorphisms do not affect disposition of budesonide in early PBC.