Modulation of gastrointestinal permeability of low-molecular-weight heparin by L-arginine: in-vivo and in-vitro evaluation.
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.
Motlekar
Nusrat Abbas
NA
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
Srivenugopal
Kalkunte Srirangachar
KS
Wachtel
Mitchell S
MS
Youan
Bi-Botti Celestin
BB
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology* / Q000633:toxicity; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D041981:Gastrointestinal Tract / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D001120:Arginine; C093450:ardeparin