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Intestinal and hepatic contributions to the pharmacokinetic interaction between gamithromycin and rifampicin after single‐dose and multiple‐dose administration in healthy foals
Author(s) -
Berlin S.,
Wallstabe S.,
Scheuch E.,
Oswald S.,
Hasan M.,
Wegner D.,
Grube M.,
Venner M.,
Ullrich A.,
Siegmund W.
Publication year - 2018
Publication title -
equine veterinary journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.82
H-Index - 87
eISSN - 2042-3306
pISSN - 0425-1644
DOI - 10.1111/evj.12796
Subject(s) - pharmacokinetics , rhodococcus equi , pharmacology , rifampicin , medicine , chemistry , antibiotics , biochemistry , virulence , gene
Summary Background Standard treatment of foals with severe abscessing lung infection caused by Rhodococcus equi using rifampicin and a macrolide antibiotic can be compromised by extensive inhibition and/or induction of drug metabolising enzymes (e.g. CYP3A4) and transport proteins (e.g. P‐glycoprotein), as has been shown for rifampicin and clarithromycin. The combination of rifampicin with the new, poorly metabolised gamithromycin, a long‐acting analogue of azithromycin and tulathromycin with lower pharmacokinetic interaction potential, might be a suitable alternative. Objectives To evaluate the pharmacokinetic interactions and pulmonary distribution of rifampicin and gamithromycin in healthy foals, and to investigate the cellular uptake of gamithromycin in vitro. Study design Controlled, four‐period, consecutive, single‐dose and multiple‐dose study. Methods Pharmacokinetics and lung distribution of rifampicin (10 mg/kg) and gamithromycin (6 mg/kg) were measured in nine healthy foals using LC‐MS/MS. Enzyme induction was confirmed using the 4β‐OH‐cholesterol/cholesterol ratio. Affinity of gamithromycin to drug transport proteins was evaluated in vitro using equine hepatocytes and MDCKII‐cells stably transfected with human OATP1B1, OATP1B3 and OATP2B1. Results Rifampicin significantly (P<0.05) increased the plasma exposure of gamithromycin (16.2 ± 4.77 vs. 8.57 ± 3.10 μg × h/mL) by decreasing the total body clearance. Otherwise, gamithromycin significantly lowered plasma exposure of single‐ and multiple‐dose rifampicin (83.8 ± 35.3 and 112 ± 43.1 vs. 164 ± 96.7 μg × h/mL) without a change in metabolic ratio and half‐life. Gamithromycin was identified as an inhibitor of human OATP1B1, OATP1B3 and OATP2B1 and as a substrate of OATP2B1. In addition, it was extracted by equine hepatocytes via a mechanism which could be inhibited by rifampicin. Main limitations Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated. Conclusion The plasma exposure of gamithromycin is significantly increased by co‐administration of rifampicin which is most likely caused by inhibition of hepatic elimination.