{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:48:52Z","timestamp":1762102132968,"version":"build-2065373602"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,1,8]],"date-time":"2018-01-08T00:00:00Z","timestamp":1515369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["03IPT612X (COM_DAT)","03IP612A","03IP612E (TECH_DAT)"],"award-info":[{"award-number":["03IPT612X (COM_DAT)","03IP612A","03IP612E (TECH_DAT)"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["beva.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Equine Veterinary Journal"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Standard treatment of foals with severe abscessing lung infection caused by\n                      <jats:italic>Rhodococcus equi<\/jats:italic>\n                      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\u2010glycoprotein), as has been shown for rifampicin and clarithromycin. The combination of rifampicin with the new, poorly metabolised gamithromycin, a long\u2010acting analogue of azithromycin and tulathromycin with lower pharmacokinetic interaction potential, might be a suitable alternative.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate the pharmacokinetic interactions and pulmonary distribution of rifampicin and gamithromycin in healthy foals, and to investigate the cellular uptake of gamithromycin in\u00a0vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study design<\/jats:title>\n                    <jats:p>Controlled, four\u2010period, consecutive, single\u2010dose and multiple\u2010dose study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Pharmacokinetics and lung distribution of rifampicin (10\u00a0mg\/kg) and gamithromycin (6\u00a0mg\/kg) were measured in nine healthy foals using LC\u2010MS\/MS. Enzyme induction was confirmed using the 4\u03b2\u2010OH\u2010cholesterol\/cholesterol ratio. Affinity of gamithromycin to drug transport proteins was evaluated in\u00a0vitro using equine hepatocytes and MDCKII\u2010cells stably transfected with human OATP1B1, OATP1B3 and OATP2B1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Rifampicin significantly (P&lt;0.05) increased the plasma exposure of gamithromycin (16.2\u00a0\u00b1\u00a04.77 vs. 8.57\u00a0\u00b1\u00a03.10\u00a0\u03bcg\u00a0\u00d7\u00a0h\/mL) by decreasing the total body clearance. Otherwise, gamithromycin significantly lowered plasma exposure of single\u2010 and multiple\u2010dose rifampicin (83.8\u00a0\u00b1\u00a035.3 and 112\u00a0\u00b1\u00a043.1 vs. 164\u00a0\u00b1\u00a096.7\u00a0\u03bcg\u00a0\u00d7\u00a0h\/mL) without a change in metabolic ratio and half\u2010life. 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main limitations<\/jats:title>\n                    <jats:p>Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The plasma exposure of gamithromycin is significantly increased by co\u2010administration of rifampicin which is most likely caused by inhibition of hepatic elimination.<\/jats:p>\n                  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