In situ intestinal absorption studies on low molecular weight heparin in rats using labrasol as absorption enhancer.
Oral absorption of low molecular weight heparin (LMWH) is limited by its molecular size and negative charge. Development of its oral formulations would allow outpatient treatment with LMWH and decrease the hospital expenses. Studies were aimed at evaluating Labrasol for improving intestinal absorption of LMWH. Formulations containing LMWH and Labrasol were administered to duodenum, jejunum, and ileum of the fasted rats. The doses of LMWH and Labrasol were 200 IU/kg and 50 mg/kg, respectively. Reversibility of absorption enhancing effect of Labrasol was assessed by administering LMWH to jejunum after 0.5 and 1 h of administration of Labrasol. The effect of different doses of Labrasol on LMWH absorption was studied by administering Labrasol at 50, 100, and 200 mg/kg doses. Administration of LMWH formulation tojejunum resulted in the highest plasma anti-Xa activity (0.50+/-0.03 IU/ml) compared to duodenum (0.19+/-0.03 IU/ml), and ileum (0.29 +/-0.06 IU/ml) and the anti-Xa levels were maintained above the therapeutic level for about 160 min. The absorption of LMWH was negligible when LMWH was administered at 0.5 and 1 h post-Labrasol administration. Increasing the dose of Labrasol has decreased the absorption of LMWH from jejunum. Labrasol increased the intestinal absorption of LMWH, and jejunum was found to be the best site of absorption. Intestinal membrane permeability changes induced by Labrasol were transient and reversible. Maintaining high drug concentration gradient across intestinal wall is important to obtain increased intestinal LMWH absorption.
Rama Prasad
Y V
YV
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan. drprasadyv@yahoo.com
Minamimoto
Takashi
T
Yoshikawa
Yukako
Y
Shibata
Nobuhito
N
Mori
Saori
S
Matsuura
Akihiro
A
Takada
Kanji
K
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004655:Emulsions / Q000494:pharmacology*; D005215:Fasting; D005989:Glycerides; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D009930:Organic Chemicals; D051381:Rats; D017208:Rats, Wistar
D000925:Anticoagulants; D004655:Emulsions; D005989:Glycerides; D006495:Heparin, Low-Molecular-Weight; D009930:Organic Chemicals; C440220:Labrasol; C080945:parnaparin