Berlin S, Wallstabe S, Scheuch E, Oswald S, Hasan M, Wegner D, Grube M, Venner M, Ullrich A, Siegmund W
Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald, Greifswald, Germany.
Lewitz Stud, Neustadt-Glewe, Germany.
Equine Vet J. 2018 Jul;50(4):525-531. doi: 10.1111/evj.12796. Epub 2018 Jan 8.
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.
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.
Controlled, four-period, consecutive, single-dose and multiple-dose study.
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.
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.
Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated.
The plasma exposure of gamithromycin is significantly increased by co-administration of rifampicin which is most likely caused by inhibition of hepatic elimination.
如利福平和克拉霉素所示，使用利福平和大环内酯类抗生素对患有马红球菌引起的严重肺脓肿感染的幼驹进行标准治疗，可能会因药物代谢酶（如CYP3A4）和转运蛋白（如P-糖蛋白）的广泛抑制和/或诱导而受到影响。利福平与新的、代谢缓慢的加米霉素（阿奇霉素和泰拉霉素的长效类似物，药代动力学相互作用潜力较低）联合使用，可能是一种合适的替代方案。
评估利福平和加米霉素在健康幼驹体内的药代动力学相互作用和肺部分布，并在体外研究加米霉素的细胞摄取情况。
对照、四期、连续、单剂量和多剂量研究。
使用液相色谱-串联质谱法（LC-MS/MS）在9只健康幼驹中测量利福平（10mg/kg）和加米霉素（6mg/kg）的药代动力学和肺部分布。使用4β-羟基胆固醇/胆固醇比值确认酶诱导情况。使用马肝细胞和稳定转染人OATP1B1、OATP1B3和OATP2B1的MDCKII细胞在体外评估加米霉素与药物转运蛋白的亲和力。
利福平通过降低全身清除率显著（P<0.05）增加了加米霉素的血浆暴露量（16.2±4.77对8.57±3.10μg×h/mL）。否则，加米霉素显著降低了单剂量和多剂量利福平的血浆暴露量（83.8±35.3和112±43.1对164±96.7μg×h/mL），而代谢比和半衰期没有变化。加米霉素被鉴定为人类OATP1B1、OATP1B3和OATP2B1的抑制剂以及OATP2B1的底物。此外，它通过一种可被利福平抑制的机制被马肝细胞摄取。
未评估加米霉素对利福平肺部分布的影响。
利福平与加米霉素联合给药显著增加了加米霉素的血浆暴露量，这很可能是由于肝脏消除受到抑制所致。
