title: Influence of CYP3A4, CYP3A5, and ABCB1 genotype and expression on budesonide pharmacokinetics: a possible role of intestinal CYP3A4 expression.
abstract: Budesonide treatment of chronic inflammatory bowel disease commonly leads to non-response or adverse reactions, possibly because of alterations in efflux transport mediated by the ABCB1 gene product P-glycoprotein or metabolism by CYP3A isoenzymes. Two groups, each consisting of nine healthy volunteers, one with the CYP3A5(*)1/(*)3 genotype (expressors) and the other with the CYP3A5(*)3/(*)3 genotype (non-expressors), were given a single oral dose of 9 mg budesonide. Plasma and urine concentrations of budesonide and its major metabolites were determined using liquid chromatography-tandem mass spectrometry. Subsequently, rectosigmoidal biopsies were taken for analysis of messenger RNA (mRNA) expression. Budesonide pharmacokinetics did not differ between genotype groups. However, intestinal CYP3A4 expression was shown to correlate directly with partial metabolic clearances of 16-hydroxy-prednisolone (r(2) = 0.30; P = 0.010) and 6-hydroxy-budesonide (r(2) = 0.25; P = 0.016), but inversely with budesonide AUC(0-24 h) (r(2) = 0.18; P = 0.040). Interestingly, a strong correlation was found between CYP3A5 and ABCB1 expression in CYP3A5 expressors (r(2) = 0.79; P = 0.001). This study suggests that intestinal CYP3A4 expression has an impact on budesonide pharmacokinetics. Moreover, CYP3A5 and ABCB1 expression appears to be coregulated.
authors.affiliation: Institute of Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany. mufer@pharmakologie.uni-kiel.de
authors.forename: M
authors.initials: M
authors.lastname: Ufer
authors.forename: K
authors.initials: K
authors.lastname: Dilger
authors.forename: L
authors.initials: L
authors.lastname: Leschhorn
authors.forename: Lm
authors.initials: L
authors.lastname: Daufresne
authors.forename: I
authors.initials: I
authors.lastname: Mosyagin
authors.forename: P
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: R
authors.initials: R
authors.lastname: Haesler
authors.forename: T
authors.initials: T
authors.lastname: Kuehbacher
authors.forename: S
authors.initials: S
authors.lastname: Nikolaus
authors.forename: S
authors.initials: S
authors.lastname: Schreiber
authors.forename: I
authors.initials: I
authors.lastname: Cascorbi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000284:Administration, Oral; D000328:Adult; D019819:Budesonide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019819:Budesonide; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human