Ledwitch Kaitlyn V, Roberts Arthur G
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 240 W. Green St., Athens, Georgia, 30602, USA.
AAPS J. 2017 Mar;19(2):409-420. doi: 10.1208/s12248-016-0023-y. Epub 2016 Dec 27.
P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that plays a major role in cardiovascular drug disposition by effluxing a chemically and structurally diverse range of cardiovascular therapeutics. Unfortunately, drug-drug interactions (DDIs) with the transporter have become a major roadblock to effective cardiovascular drug administration because they can cause adverse drug reactions (ADRs) or reduce the efficacy of drugs. Cardiovascular ion channel inhibitors are particularly susceptible to DDIs and ADRs with Pgp because they often have low therapeutic indexes and are commonly coadministered with other drugs that are also Pgp substrates. DDIs from cardiovascular ion channel inhibitors with the transporter occur because of inhibition or induction of the transporter and the transporter's tissue and cellular localization. Inhibiting Pgp can increase absorption and reduce excretion of drugs, leading to elevated drug plasma concentrations and drug toxicity. In contrast, inducing Pgp can have the opposite effect by reducing the drug plasma concentration and its efficacy. A number of in vitro and in vivo studies have already demonstrated DDIs from several cardiovascular ion channel inhibitors with human Pgp and its animal analogs, including verapamil, digoxin, and amiodarone. In this review, Pgp-mediated DDIs and their effects on pharmacokinetics for different categories of cardiovascular ion channel inhibitors are discussed. This information is essential for improving pharmacokinetic predictions of cardiovascular therapeutics, for safer cardiovascular drug administration and for mitigating ADRs emanating from Pgp.
P-糖蛋白（Pgp）是一种ATP结合盒（ABC）转运蛋白，通过外排多种化学结构各异的心血管治疗药物，在心血管药物处置中发挥主要作用。不幸的是，与该转运蛋白的药物相互作用（DDIs）已成为有效进行心血管药物给药的主要障碍，因为它们可能导致药物不良反应（ADRs）或降低药物疗效。心血管离子通道抑制剂尤其容易与Pgp发生药物相互作用和不良反应，因为它们通常治疗指数较低，且常与其他也是Pgp底物的药物联合使用。心血管离子通道抑制剂与该转运蛋白之间的药物相互作用是由于对转运蛋白的抑制或诱导以及转运蛋白的组织和细胞定位所致。抑制Pgp可增加药物吸收并减少排泄，导致药物血浆浓度升高和药物毒性。相反，诱导Pgp则会降低药物血浆浓度及其疗效，产生相反的效果。多项体外和体内研究已经证明，几种心血管离子通道抑制剂与人Pgp及其动物类似物之间存在药物相互作用，包括维拉帕米、地高辛和胺碘酮。在本综述中，将讨论Pgp介导的药物相互作用及其对不同类别的心血管离子通道抑制剂药代动力学的影响。这些信息对于改善心血管治疗药物的药代动力学预测、实现更安全的心血管药物给药以及减轻由Pgp引起的不良反应至关重要。
