Chitosans as absorption enhancers for poorly absorbable drugs. 1: Influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (Caco-2) cells.
OBJECTIVE
Chitosan has recently been demonstrated to effectively enhance the absorption of hydrophilic drugs such as peptides and proteins across nasal and intestinal epithelia (1-3). In this study, the effect of the chemical composition and molecular weight of chitosans on epithelial permeability and toxicity was investigated using monolayers of human intestinal epithelial Caco-2 cells as a model epithelium.


METHODS
Eight chitosans varying in degree of acetylation (DA) and molecular weight were studied. The incompletely absorbed hydrophilic marker molecule 14C-mannitol was used as a model drug to assess absorption enhancement. Changes in intracellular dehydrogenase activity and cellular morphology were used to assess toxicity.


RESULTS
Chitosans with a low DA (1 and 15%) were active as absorption enhancers at low and high molecular weights. However, these chitosans displayed a clear dose-dependent toxicity. Chitosans with DAs of 35 and 49% enhanced the transport of 14C-mannitol at high molecular weights only, with low toxicity. One chitosan (DA = 35%; MW = 170 kD) was found to have especially advantageous properties such as an early onset of action, very low toxicity, and a flat dose-absorption enhancement response relationship.


CONCLUSIONS
The structural features of chitosans determining absorption enhancement are not correlated with those determining toxicity, which makes it possible to select chitosans with maximal effect on absorption and minimal toxicity.
Schipper
N G
NG
Department of Pharmaceutics, Uppsala University, Sweden.
Vårum
K M
KM
Artursson
P
P
D000107:Acetylation; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002686:Chitin / Q000031:analogs & derivatives* / Q000494:pharmacology; D048271:Chitosan; D004234:Diuretics, Osmotic / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008353:Mannitol / Q000493:pharmacokinetics; D008970:Molecular Weight; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D002250:Carbon Radioisotopes; D004234:Diuretics, Osmotic; D002686:Chitin; D008353:Mannitol; D048271:Chitosan; D010088:Oxidoreductases