title: Clarithromycin is absorbed by an intestinal uptake mechanism that is sensitive to major inhibition by rifampicin: results of a short-term drug interaction study in foals.
abstract: Pulmonary penetration of clarithromycin (CLR) in epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALCs) can be influenced by CYP3A4, by P-glycoprotein, and, according to our hypothesis, by a member of the organic anion-transporting protein (OATP) family, for which rifampicin (RIF) is inhibiting in single doses but inducing after long-term coadministration. To assess the partial inhibitory effect, we measured absorption and pulmonary distribution of CLR after short-term (2.5-day) coadministration of RIF, after which up-regulation is not expected. The drug interaction study was performed with five doses (12-h interval) of CLR (7.5 mg/kg) and RIF (10 mg/kg) in nine healthy foals; horse transporters are very similar in protein sequence and transcriptional regulation to the human analogs. RIF was equally distributed in ELF but reached half the plasma levels in BALCs. The deacetylated metabolite accumulated 1.4- to 6-fold in ELF and 8- to 60-fold in BALCs. CLR did not significantly influence the distribution of RIF. CLR and 14-hydroxyclarithromycin (14OH-CLR) accumulated approximately 20- to 40-fold and 1.5- to 4.5-fold in ELF and 300- to 1800-fold and 25- to 90-fold in BALCs, respectively. With RIF, plasma levels of CLR decreased by more than 70% without changes in 14OH-CLR formation, the half-lives of CLR and 14OH-CLR, and the 4β-hydroxycholesterol/cholesterol ratio (a surrogate for CYP3A4 induction). CLR was an inhibitor of OATP1B3 (IC(50) = 9.50 ± 3.50 μM), OATP1B1 (IC(50) = 46.0 ± 2.27 μM), OATP1A2 (IC(50) = 92.6 ± 1.49 μM), and OATP2B1 (IC(50) = 384 ± 5.30 μM) but was not a substrate for these transporters in transfected human embryonic kidney cells. In conclusion, despite having no significant inducing effects, RIF decreased plasma levels of CLR below the minimal inhibitory concentration required to inhibit 90% of growth of pathogenic bacteria, most likely through inhibition of an unknown intestinal uptake transporter.
authors.affiliation: Department of Clinical Pharmacology, Ernst Moritz Arndt University, Felix-Hausdorff-Str. 3, D-17487 Greifswald, Germany.
authors.forename: Jette
authors.initials: J
authors.lastname: Peters
authors.forename: Karen
authors.initials: K
authors.lastname: Eggers
authors.forename: Stefan
authors.initials: S
authors.lastname: Oswald
authors.forename: Wiebke
authors.initials: W
authors.lastname: Block
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Marc
authors.initials: M
authors.lastname: Lämmer
authors.forename: Monica
authors.initials: M
authors.lastname: Venner
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
mesh_terms: D000818:Animals; D017291:Clarithromycin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D057809:HEK293 Cells; D006736:Horses; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology*; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D027361:Organic Anion Transporters; C056228:14-hydroxyclarithromycin; D017291:Clarithromycin; D012293:Rifampin