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.

The research highlights how the absorption of the antibiotic Clarithromycin (CLR) in horses’ intestines may be severely inhibited by the drug rifampicin (RIF) and this inhibition could lead to decreased effectiveness in treating infections.

Research Objective and Hypothesis

• The aim of the research was to investigate the impact of rifampicin (RIF) on the absorption and distribution of clarithromycin (CLR).
• The researchers hypothesized that CLR absorption could be influenced by a protein (OATP) that RIF inhibits in single doses and induces after long-term administration.

Methodology and Results

• A drug interaction study was performed using five doses of CLR and RIF in nine healthy young horses (foals). This approach was chosen because horse transporters are very close in protein sequence and transcriptional regulation to the human analogs.
• The results showed that RIF was evenly distributed in the horses’ bronchoalveolar lavages (BALs) but reached only half the plasma levels in BAL cells. The metabolite of CLR increased between 1.4 to 6 times in ELF and 8 to 60 times in BAL cells.
• With RIF, plasma levels of CLR decreased by over 70% without influencing the formation of 14-hydroxyclarithromycin (14OH-CLR), CLR’s half-lives, and the 4β-hydroxycholesterol/cholesterol ratio, an indicator of CYP3A4 induction.
• CLR was found to inhibit several OATP proteins but was not a substrate for these transporters in human embryonic kidney cells. The inhibition of OATP proteins is important as these proteins are involved in the transport of numerous drugs, hormones, and other substances.
• The results confirm the initial hypothesis that CLR absorption could be inhibited by RIF, which likely works through the inhibition of an unclassified intestinal transporter.

Conclusions

• The findings imply that RIF decreases the plasma level of CLR. That reduction of CLR in plasma interferes with its concentration required to inhibit the growth of pathogenic bacteria by 90% (minimal inhibitory concentration).
• Thus RIF, even without significant inducing effects, might compromise the effectiveness of CLR in treating infections. As such, the simultaneous use of RIF and CLR may require dosage adjustments.