Motlekar Nusrat Abbas, Srivenugopal Kalkunte Srirangachar, Wachtel Mitchell S, Youan Bi-Botti Celestin
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
J Pharm Pharmacol. 2006 May;58(5):591-8. doi: 10.1211/jpp.58.5.0003.
L-Arginine is the principal physiological precursor of nitric oxide (NO, a key neurotransmitter) that plays a versatile role in the physiology of the gastrointestinal tract. In this study, the efficacy of L-arginine in enhancing intestinal absorption of ardeparin, a low-molecular-weight heparin (LMWH) was investigated in Caco-2 cell monolayers and a rat model. Regional permeability studies using rat intestine were performed using a modified Ussing chamber. Cell viability in the presence of various concentrations of enhancer was determined by MTT assay. Furthermore, the eventual mucosal epithelial damage was histologically evaluated. LMWH formulated with L-arginine was administered orally to male Sprague-Dawley rats and the absorption of LMWH was determined by measuring plasma anti-factor Xa activity. Higher ardeparin in-vitro permeability (approximately 3 fold) compared with control was observed in the presence of 2% L-arginine. Regional permeability studies indicated predominant absorption in the colon region. Cell viability studies showed no significant cytotoxicity below 0.8% L-arginine. The oral bioavailability of ardeparin formulated with L-arginine (250 mg kg(-1)) was increased by approximately 2 fold compared with control. The formulation was well tolerated by the rats and no abnormal histopathological findings were observed in intestinal tissues of rats exposed to L-arginine. These results suggest that L-arginine may be useful in enhancing the intestinal absorption of LMWHs.
L-精氨酸是一氧化氮（NO，一种关键神经递质）的主要生理前体，在胃肠道生理学中发挥着多方面作用。在本研究中，在Caco-2细胞单层和大鼠模型中研究了L-精氨酸增强低分子肝素（LMWH）阿地肝素肠道吸收的效果。使用改良的Ussing室对大鼠肠道进行区域通透性研究。通过MTT法测定在各种浓度增强剂存在下的细胞活力。此外，对最终的黏膜上皮损伤进行组织学评估。将与L-精氨酸配制的LMWH口服给予雄性Sprague-Dawley大鼠，并通过测量血浆抗Xa因子活性来测定LMWH的吸收。在存在2%L-精氨酸的情况下，观察到阿地肝素的体外通透性比对照高（约3倍）。区域通透性研究表明在结肠区域吸收占主导。细胞活力研究表明，在L-精氨酸浓度低于0.8%时无明显细胞毒性。与对照相比，与L-精氨酸配制的阿地肝素（250mg kg(-1)）的口服生物利用度提高了约2倍。该制剂在大鼠中耐受性良好，在暴露于L-精氨酸的大鼠肠道组织中未观察到异常组织病理学发现。这些结果表明，L-精氨酸可能有助于增强LMWH的肠道吸收。
