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Modulation of gastrointestinal permeability of low-molecular-weight heparin by L-arginine: in-vivo and in-vitro evaluation.

Authors
  • Motlekar, Nusrat Abbas
  • Srivenugopal, Kalkunte Srirangachar
  • Wachtel, Mitchell S
  • Youan, Bi-Botti Celestin
Type
Published Article
Journal
The Journal of pharmacy and pharmacology
Publication Date
May 01, 2006
Volume
58
Issue
5
Pages
591–598
Identifiers
PMID: 16640827
Source
Medline
License
Unknown

Abstract

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.

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