Al Shaker Hanadi A, Qinna Nidal A, Badr Mujtaba, Al Omari Mahmoud M H, Idkaidek Nasir, Matalka Khalid Z, Badwan Adnan A
Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.
Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan; University of Petra Pharmaceutical Center (UPPC), Amman, Jordan.
Eur J Pharm Sci. 2017 Jul 15;105:137-143. doi: 10.1016/j.ejps.2017.05.012. Epub 2017 May 11.
Propranolol (PROP) undergoes extensive first-pass metabolism by the liver resulting in a relatively low bioavailability (13-23%); thus, multiple oral doses are required to achieve therapeutic effect. Since some studies have reported that glucosamine (GlcN) can increase the bioavailability of some drugs, therefore, it is aimed to study whether GlcN can change the pharmacokinetic parameters of PROP, thus modulating its bioavailability. When PROP was orally co-administered with GlcN (200mg/kg) to rats, PROP area under curve (AUC) and maximum concentration (C) were significantly decreased by 43% (p<0.01) and 33% (p<0.05), respectively. In line with the in vivo results, in silico simulations confirmed that GlcN decreased rat intestinal effective permeability (P) and increased PROP clearance by 50%. However, in situ single pass intestinal perfusion (SPIP) experiments showed that GlcN significantly increased PROP serum levels (p<0.05). Furthermore, GlcN decreased PROP disposition/distribution into cultured hepatocytes in concentration dependent manner. Such change in the interaction pattern between GlcN and PROP might be attributed to the environment of the physiological buffer used in the in vitro experiments (pH7.2) versus the oral administration and thus, enhanced PROP permeability. Nevertheless, such enhancement was not detected when everted gut sacks were incubated with both drugs at the same pH in vitro. In conclusion, GlcN decreased PROP serum levels in rats in a dose-dependent manner. Such interaction might be attributed to decreased intestinal permeability and enhanced clearance of PROP in the presence of GlcN. Further investigations are still warranted to explain the in vitro inhibitory action of GlcN on PROP hepatocytes disposition and the involvement of GlcN in the intestinal and hepatic metabolizing enzymes of PROP at different experimental conditions.
普萘洛尔（PROP）在肝脏中经历广泛的首过代谢，导致生物利用度相对较低（13%-23%）；因此，需要多次口服给药才能达到治疗效果。由于一些研究报道氨基葡萄糖（GlcN）可以提高某些药物的生物利用度，因此，旨在研究GlcN是否可以改变PROP的药代动力学参数，从而调节其生物利用度。当将PROP与GlcN（200mg/kg）一起口服给予大鼠时，PROP的曲线下面积（AUC）和最大浓度（C）分别显著降低了43%（p<0.01）和33%（p<0.05）。与体内结果一致，计算机模拟证实GlcN降低了大鼠肠道有效渗透率（P），并使PROP清除率提高了50%。然而，原位单通道肠道灌注（SPIP）实验表明，GlcN显著提高了PROP的血清水平（p<0.05）。此外，GlcN以浓度依赖的方式降低了PROP在培养肝细胞中的处置/分布。GlcN与PROP之间相互作用模式的这种变化可能归因于体外实验中使用的生理缓冲液环境（pH7.2）与口服给药的差异，从而增强了PROP的通透性。然而，当外翻肠囊在相同pH下体外与两种药物一起孵育时，未检测到这种增强作用。总之，GlcN以剂量依赖的方式降低了大鼠体内PROP的血清水平。这种相互作用可能归因于在存在GlcN的情况下肠道通透性降低和PROP清除率提高。仍有必要进行进一步研究，以解释GlcN对PROP肝细胞处置的体外抑制作用，以及GlcN在不同实验条件下参与PROP的肠道和肝脏代谢酶的情况。
