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首页> 外文期刊>Journal of Parasitology >Resistance-induced changes in triclabendazole transport in Fasciola hepatica: ivermectin reversal effect
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Resistance-induced changes in triclabendazole transport in Fasciola hepatica: ivermectin reversal effect

机译：抗性诱导的费西拉肝片中三苯达唑运输的变化：伊维菌素逆转作用

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Triclabendazole (TCBZ) and albendazole (ABZ) are flukicidal benzimidazole compounds extensively used in veterinary medicine. Although TCBZ has excellent activity against mature and immature stages of the liver fluke, Fasciola hepatica, ABZ action is restricted to flukes older than 12 wk. The intensive use of TCBZ has resulted in the development of resistance. To gain insight into the mechanisms of resistance to TCBZ, the ex vivo diffusion of TCBZ, TCBZ sulfoxide (TCBZSO, the active metabolite of TCBZ), and ABZ into TCBZ-susceptible and -resistant adult flukes was compared. TCBZ-susceptible (Cullompton) and -resistant (Sligo) flukes were incubated in Krebs-Ringer Tris buffer with either TCBZ, TCBZSO, or ABZ (5 nmol/ ml) for 90 min. Drug/metabolite concentrations were quantified by high-performance liquid chromatography. All the assayed molecules penetrated through the tegument of both susceptible and resistant flukes. However, significantly lower concentrations of TCBZ and TCBZSO were recovered within the TCBZ-resistant flukes. In contrast, ABZ entrance into the susceptible and resistant flukes was equivalent. The influx/efflux balance for TCBZ, TCBZSO, and ABZ in susceptible and resistant flukes in the presence or absence of a substrate (ivermectin) of the drug transporter P-glycoprotein was assessed. The ivermectin-induced modulation of P-glycoprotein activity decreased TCBZ efflux from the resistant flukes. Higher concentrations of TCBZ and TCBZSO were recovered from the resistant liver flukes in the presence of ivermectin. Thus, an altered influx/efflux mechanism may account for the development of resistance to TCBZ in F. hepatica.
机译：曲卡苯达唑（TCBZ）和阿苯达唑（ABZ）是兽药中广泛使用的杀细菌性苯并咪唑化合物。尽管TCBZ具有抗肝吸虫Fasciola hepatica成熟和不成熟阶段的出色活性，但ABZ作用仅限于12周龄以上的吸虫。大量使用TCBZ导致了抗药性的发展。为了深入了解对TCBZ的耐药机制，比较了TCBZ，TCBZ亚砜（TCBZSO，TCBZ的活性代谢产物）和ABZ在TCBZ易感和耐药的成年吸虫中的离体扩散。将TCBZ敏感（Cullompton）和抗性（Sligo）吸管在含有TCBZ，TCBZSO或ABZ（5 nmol / ml）的Krebs-Ringer Tris缓冲液中孵育90分钟。药物/代谢物浓度通过高效液相色谱法定量。所有检测到的分子均通过易感性和抗性吸虫的外皮渗透。但是，在抗TCBZ的吸虫中回收的TCBZ和TCBZSO的浓度明显降低。相反，ABZ进入易感性和抗性吸虫的过程是等效的。在存在或不存在药物转运蛋白P-糖蛋白底物（伊维菌素）的情况下，评估易感性和耐药性吸虫中TCBZ，TCBZSO和ABZ的流入/流出平衡。伊维菌素诱导的P-糖蛋白活性的调节降低了抗性吸虫的TCBZ外排。在伊维菌素存在的情况下，从耐药肝吸虫中回收到更高浓度的TCBZ和TCBZSO。因此，改变的流入/流出机制可能解释了肝小球藻对TCBZ的抗性发展。

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