Intestinal and hepatic contributions to the pharmacokinetic interaction between gamithromycin and rifampicin after single-dose and multiple-dose administration in healthy foals.

This is a study examining the drug interaction between gamithromycin and rifampicin, commonly used to treat severe lung infection in foals. It investigates how these drugs influence each other’s pharmacokinetics and absorption in the body.

Research Purpose and Methods

• The goal of this paper was to investigate how the two antibiotics, gamithromycin and rifampicin, interact when given to healthy foals, and how this influences their dispersion in the body. The researchers also wanted to study the cellular absorption of gamithromycin in vitro.
• The study was carried out in a controlled, four-period consecutive span, with single and multiple dose administration.
• The substances’ pharmacokinetics and lung distribution were measured in nine healthy foals, using the Liquid Chromatography coupled with tandem mass spectrometry (LC-MS/MS) technique. Liver enzyme induction was confirmed via the 4β-OH-cholesterol/cholesterol ratio.
• Affinity of gamithromycin to drug transport proteins was assessed in a test tube using equine liver cells (hepatocytes) and a specific strain of cells (MDCKII) that had been stably transfected with human proteins OATP1B1, OATP1B3, and OATP2B1.

Study Results

• Rifampicin was found to significantly increase the plasma exposure of gamithromycin (16.2 ± 4.77 vs. 8.57 ± 3.10 μg × h/mL) by decreasing the total body clearance of the drug. This indicates that rifampicin might inhibit the body’s ability to metabolize and eliminate gamithromycin, leading to increased levels of gamithromycin in the bloodstream.
• Conversely, gamithromycin significantly lowered plasma exposure of both, single and multiple-dose rifampicin (83.8 ± 35.3 and 112 ± 43.1 vs. 164 ± 96.7 μg × h/mL), without a change in its metabolic ratio and half-life. This suggests that gamithromycin might decrease the absorption or increase the elimination of rifampicin in the body.
• Further testing showed that gamithromycin inhibits human proteins OATP1B1, OATP1B3, and OATP2B1 and acts as a substrate of OATP2B1. It is also absorbed by equine liver cells via a process that could be inhibited by rifampicin.

Conclusions

• The study did not evaluate the influence of gamithromycin on the pulmonary distribution of rifampicin.
• On the whole, it was concluded that the plasma exposure of gamithromycin is significantly increased by co-administration of rifampicin, most likely due to inhibition of hepatic elimination of the drug, making it remain longer in the bloodstream.