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.


CONCLUSIONS
Common MDR1 gene polymorphisms do not affect disposition of budesonide in early PBC.
Dilger
Karin
K
Dr. Falk Pharma GmbH, Freiburg, Germany.
Cascorbi
Ingolf
I
Grünhage
Frank
F
Hohenester
Simon
S
Sauerbruch
Tilman
T
Beuers
Ulrich
U
D000284:Administration, Oral; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D019819:Budesonide / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR / Q000187:drug effects* / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D019819:Budesonide; D051544:Cytochrome P-450 CYP3A