In Vitro CYP2D Inhibitory Effect and Influence on Pharmacokinetics and Pharmacodynamic Parameters of Metoprolol Succinate by Terminalia arjuna in Rats.

Drug metabolism letters Pub Date : 2016-05-31 DOI:10.2174/1872312810666160219121415

A. Varghese, J. Savai, Shruti Mistry, Preeti K. Khandare, K. Barve, N. Pandita, R. Gaud

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引用次数: 1

Abstract

BACKGROUND Terminalia arjuna Wight & Arn. (Combretaceae) is a tree having an extensive medicinal potential in cardiovascular disorders. T. arjuna bark extract has been reported to play a significant role as a cardiac stimulant for its beneficial effects in angina. Herb - drug interactions (HDI) are one of the most important clinical concerns in the concomitant consumption of herbs and prescription drugs. Our study was to investigate the in vitro CYP2D inhibition potential of Terminalia arjuna (T. arjuna) extracts in rat liver microsomes and to study the influence of aqueous bark extract of T. arjuna on the oral pharmacokinetics and pharmacodynamics of metoprolol succinate in rats. METHODS The CYP2D inhibition potential of herbal extracts of T. arjuna was investigated in rat liver microsomes. Pharmacokinetic-pharmacodynamic interaction of aqueous extract of T. arjuna with metoprolol succinate was investigated in rats. RESULTS The ethyl acetate, alcoholic & aqueous bark extracts of T. arjuna showed potent reversible non-competitive inhibition CYP2D enzyme in rat liver microsomes with IC50 values less than 40 μg/mL. Arjunic acid, arjunetin and arjungenin did not show significant inhibition of CYP2D enzyme in rat liver microsomes. Pharmacokinetic studies showed that aqueous bark extract of T. arjuna led to a significant reduction (P < 0.05) in AUC0-24h and Cmax of metoprolol succinate in rats, when co-administered. Pharmacodynamic studies reveal a significant reduction in therapeutic activity of metoprolol succinate on co-administration with aqueous bark extract of T. arjuna. CONCLUSION Based on our in vitro and in vivo findings and until further clinical drug interaction experiments are conducted, the co-administration of drugs, especially those primarily cleared via CYP2D catalyzed metabolism, with T. arjuna extracts should be done with caution.

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阿终对琥珀酸美托洛尔大鼠体外CYP2D抑制作用及对药动学和药效学参数的影响。

背景:arjuna wright & Arn。(菊科)是一种在心血管疾病中具有广泛药用潜力的树。据报道，阿朱那树皮提取物作为一种心脏兴奋剂对心绞痛有显著的有益作用。中药与药物相互作用(HDI)是中药与处方药同时使用中最重要的临床问题之一。本研究旨在研究阿朱那(T. arjuna)提取物在大鼠肝微粒体中的体外CYP2D抑制潜力，并研究阿朱那树皮水提物对琥珀酸美托洛尔大鼠口服药动学和药效学的影响。方法以大鼠肝微粒体为实验对象，研究阿朱那中草药提取物对CYP2D的抑制作用。在大鼠体内研究了阿朱那水提物与琥珀酸美托洛尔的药动学相互作用。结果苦参树皮乙酸乙酯、醇提物和水提物对大鼠肝微粒体CYP2D酶有较强的可逆非竞争性抑制作用，IC50值均小于40 μg/mL。Arjunic acid、arjunetin和arjungenin对大鼠肝微粒体CYP2D酶无明显抑制作用。药代动力学研究表明，麻树树皮水提物可显著降低大鼠AUC0-24h和琥珀酸美托洛尔Cmax (P < 0.05)。药效学研究表明，琥珀酸美托洛尔与阿朱那树皮水提取物共给药可显著降低治疗活性。结论根据我们体外和体内的研究结果，在进一步的临床药物相互作用实验进行之前，药物，特别是那些主要通过CYP2D催化代谢清除的药物，与阿朱那提取物共同给药应谨慎。

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Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.