Pharmacokinetics of Dasatinib in Rats: a Potential Food-Drug Interaction with Naringenin.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Mohammad Raish, Ajaz Ahmad, Badr Abdul Karim, Yousef A Bin Jardan, Abdul Ahad, Muzaffar Iqbal, Khalid M Alkharfy, Fahad I Al-Jenoobi, Omer Mansour Mohammed
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引用次数: 0

Abstract

Background and objectives: The novel tyrosine kinase inhibitor (TKI) dasatinib, a multitarget inhibitor of Bcr-Abl and Src family kinases, has been licensed for the treatment of Ph+ acute lymphoblastic leukemia and chronic myeloid leukemia. Many citrus-based foods include the flavonoid naringenin, which is commonly available. Dasatinib is a Cyp3a4, P-gp, and Bcrp1 substrate, which makes it sensitive to potential food-drug interactions. The concurrent use of naringenin may change the pharmacokinetics of dasatinib, which could result in adverse effects and toxicity. The present investigation examined the impact of naringenin on the pharmacokinetics interactions of DAS and proposes a possible interaction mechanism in Wistar rats.

Methods: Rats were provided with a single oral dose of dasatinib (25 mg/kg) with or without naringenin pretreatment (150 mg/kg p.o. daily for 7 days, n = 6 in each group). Dasatinib was quantified in plasma by UHPLC MS/MS assay. Noncompartmental analysis was used to compute the pharmacokinetic parameters, and immunoblot was used to assess the protein expression in the hepatic and intestinal tissues.

Results: Following 7 days of naringenin pretreatment, the plasma mean concentration of dasatinib was enhanced compared with without pretreatment. In rats that were pretreated with naringenin, the pharmacokinetics of the orally administered dasatinib (25 mg/kg) was shown to be significantly different from that of dasatinib given without pretreatment (p < 0.05). There was a significant enhancement in pharmacokinetic parameters elimination half-life (T1/2), time to maximum concentration ( Tmax), maximum concentration )Cmax), area under the concentration-time curve (AUC0-t), area under the moment curve (AUMC0-∞), and mean residence time (MRT) by 28.41%, 50%, 103.54%, 72.64%, 115.08%, and 15.19%, respectively (p < 0.05) and suppression in elimination rate constant (Kel), volume of distribution (Vd), and clearance (CL) by 21.09%, 31.13%, and 46.25%, respectively, in comparison with dasatinib alone group (p < 0.05). The enhancement in dasatinib bioavailability and systemic exposure resulted from the significant inhibition of Cyp3a2, Mdr1/P-gp, and Bcrp1 expression and suppression of the dasatinib hepatic and intestinal metabolism, which enhanced the rate of dasatinib absorption and decreased its elimination.

Conclusion: Concurrent use of naringenin-containing supplements, herbs, or foods with dasatinib may cause serious and potentially life-threatening drug interactions. Further studies are necessary to determine the clinical significance of these findings.

Abstract Image

大鼠体内达沙替尼的药代动力学:与柚皮苷的潜在食物-药物相互作用
背景和目的:新型酪氨酸激酶抑制剂(TKI)达沙替尼是Bcr-Abl和Src家族激酶的多靶点抑制剂,已被授权用于治疗Ph+急性淋巴细胞白血病和慢性粒细胞白血病。许多柑橘类食品都含有黄酮类物质柚皮苷,这种物质很常见。达沙替尼是Cyp3a4、P-gp和Bcrp1底物,因此对潜在的食物-药物相互作用很敏感。同时使用柚皮素可能会改变达沙替尼的药代动力学,从而导致不良反应和毒性。本研究考察了柚皮苷对 DAS 药代动力学相互作用的影响,并提出了 Wistar 大鼠可能的相互作用机制:方法:给大鼠口服单剂量达沙替尼(25 mg/kg),无论是否经过柚皮素预处理(每天150 mg/kg,口服,共7天,每组6只)。血浆中的达沙替尼通过超高效液相色谱 MS/MS 法进行定量。非室分析用于计算药代动力学参数,免疫印迹用于评估肝脏和肠道组织中的蛋白质表达:结果:柚皮苷预处理7天后,达沙替尼的血浆平均浓度比未预处理时有所提高。大鼠口服达沙替尼(25 mg/kg)后,其药代动力学与未经预处理的达沙替尼相比有显著差异(p < 0.05)。药代动力学参数消除半衰期(T1/2)、达到最大浓度时间(Tmax)、最大浓度(Cmax)、浓度-时间曲线下面积(AUC0-t)、矩曲线下面积(AUMC0-∞)和平均停留时间(MRT)分别明显提高28.与单用达沙替尼组相比,消除速率常数(Kel)、分布容积(Vd)和清除率(CL)分别降低了 21.09%、31.13% 和 46.25%(P < 0.05)。达沙替尼生物利用度和全身暴露量的增加是由于Cyp3a2、Mdr1/P-gp和Bcrp1的表达受到显著抑制,达沙替尼的肝肠代谢受到抑制,从而提高了达沙替尼的吸收率,降低了其消除率:结论:与达沙替尼同时使用含有柚皮苷的补充剂、草药或食物可能会导致严重的、潜在的危及生命的药物相互作用。有必要开展进一步研究,以确定这些发现的临床意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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