title: Pharmacokinetics and Pulmonary Distribution of Clarithromycin and Rifampicin after Concomitant and Consecutive Administration in Foals.
abstract: Drug interactions often result from multiple pharmacokinetic changes, such as after rifampicin (RIF) and clarithromycin (CLA) in the treatment of abscessing lung diseases. Comedication of RIF may interact with CLA disposition by either induction of presystemic elimination processes and/or inhibition of uptake mechanisms because it regulates gene transcription and modulates function of various CYP enzymes, multidrug efflux and uptake transporters for which CLA is a substrate. To distinguish the transcriptional changes from the modulating interaction components upon CLA absorption and pulmonary distribution, we initiated a repeated-dose study in 12 healthy foals with CLA (7.5 mg/kg, p.o., b.i.d.) in comedication with RIF (10 mg/kg, p.o., b.i.d.) given either concomitantly with CLA or consecutively 4 h after CLA. Affinity of CLA to human P-gp, MRP2, and MRP3 and to OCT1, OCT3, and PEPT1 was measured using Sf9-derived inside-out membrane vesicles and transfected HEK293 cells, respectively. ABCB1 (P-gp) induction by RIF and affinity of CLA to equine P-gp were studied using primary equine hepatocytes. Absolute bioavailability of CLA was reduced from ∼40% to below 5% after comedication of RIF in both schedules of administration, and Tmax occurred ∼2-3 h earlier. The loss of bioavailability was not associated with increased 14-hydroxyclarithromycin (14-OH-CLA) exposure. After consecutive dosing, absolute bioavailability and pulmonary penetration of CLA increased ∼2-fold compared to concomitant use. In vitro, CLA showed affinity to human and equine P-gp. Expression of ABCB1 mRNA was upregulated by RIF in 7 of 8 duodenal biopsy specimens and in primary equine hepatocytes. In conclusion, the major undesired influence of RIF on oral absorption and pulmonary distribution of CLA is associated with induction of intestinal P-gp. Consecutive administration to avoid competition with its intestinal uptake transport results in significantly, although not clinically relevant, improved systemic exposure.
authors.affiliation: Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald , Greifswald, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Berlin
authors.affiliation: Lewitz Stud , Neustadt-Glewe, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Spieckermann
authors.affiliation: Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald , Greifswald, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Oswald
authors.affiliation: Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald , Greifswald, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Keiser
authors.affiliation: Lewitz Stud , Neustadt-Glewe, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lumpe
authors.affiliation: PRIMACYT Cell Culture Technology GmbH , Schwerin, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: Department of General Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald , Greifswald, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.affiliation: Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald , Greifswald, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Hasan
authors.affiliation: Veterinary Clinic for Horses , Destedt, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Venner
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D057809:HEK293 Cells; D006736:Horses; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000904:Antibiotics, Antitubercular; D017291:Clarithromycin; D012293:Rifampin
keywords: P-glycoprotein (P-gp); Rhodococcus equi; clarithromycin; drug−drug interaction (DDI); foals; pharmacokinetics; rifampicin