title: Polyamidoamine dendrimers as novel potential absorption enhancers for improving the small intestinal absorption of poorly absorbable drugs in rats.
abstract: Effects of polyamidoamine (PAMAM) dendrimers on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF), fluorescein isothiocyanate-dextrans (FDs) with various molecular weights, calcitonin and insulin were used as model drugs of poorly absorbable drugs. The absorption of CF, FD4 and calcitonin from the rat small intestine was significantly enhanced in the presence of PAMAM dendrimers. The absorption-enhancing effects of PAMAM dendrimers for improving the small intestinal absorption of CF were concentration and generation dependent and a maximal absorption-enhancing effect was observed in the presence of 0.5% (w/v) G2 PAMAM dendrimer. However, G2 PAMAM dendrimer had almost no absorption-enhancing effect on the small intestinal absorption of macromolecular drugs including FD10 and insulin. Overall, the absorption-enhancing effects of G2 PAMAM dendrimer in the small intestine decreased as the molecular weights of drug increased. However, G2 PAMAM dendrimer did not enhance the intestinal absorption of these drugs with different molecular weights in the large intestine. Furthermore, we evaluated the intestinal membrane damage with or without G2 PAMAM dendrimer. G2 PAMAM dendrimer (0.5% (w/v)) significantly increased the activities of lactate dehydrogenase (LDH) and the amounts of protein released from the intestinal membranes, but the activities and amounts of these toxic markers were less than those in the presence of 3% Triton X-100 used as a positive control. Moreover, G2 PAMAM dendrimer at concentrations of 0.05% (w/v) and 0.1% (w/v) did not increase the activities and amounts of these toxic markers. These findings suggested that PAMAM dendrimers at lower concentrations might be potential and safe absorption enhancers for improving absorption of poorly absorbable drugs from the small intestine.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Lin
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujimori
authors.forename: Naoko
authors.initials: N
authors.lastname: Kawaguchi
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Tsujimoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Nishimi
authors.forename: Zhengqi
authors.initials: Z
authors.lastname: Dong
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D050091:Dendrimers / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D004364:Pharmaceutical Preparations; D007770:L-Lactate Dehydrogenase