Multidrug resistance 1 genotype and disposition of budesonide in early primary biliary cirrhosis

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 (2,677G>T,A and 3,435C>T) on disposition of a single oral dose of 3 mg budesonide. CYP3A5 gene polymorphisms (6,986A>G) were analyzed in parallel. RESULTS: In MDR1 2,677 GG and 3,435 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 3,435 CC with putatively high intestinal expression of P-glycoprotein than in MDR1 3,435 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