Herb-Drug Interactions: Chitosan

Types, sources and related compounds

Poliglusam.

Pharmacopoeias

Chitosan Hydrochloride (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4).

Constituents

Chitosan is a polysaccharide composed of polymers of glucosamine and N-acetylglucosamine. It is obtained from the partial deacetylation of chitin obtained from the shells of crustaceans such as shrimps and crabs. It is available in different molecular weights, viscosity grades and degrees of deacetylation.

Use and indications

Chitosan is used as a dietary supplement for obesity and hypercholesterolaemia. Pharmaceutically, chitosan and various derivatives are used, or being investigated, as excipients in drug formulations including oral or nasal dosage forms and gene carrier systems.

Pharmacokinetics

Chitosan is an absorption enhancer and increases the permeability of peptide drugs across intestinal and mucosal epithelia, which has implications for drug delivery systems. A thiolated chitosan derivative is also reported to inhibit the activity of P-glycoprotein, which has possible applications for improving the bioavailability of P-glycoprotein substrates, but note that this derivative does not appear to be used as a dietary supplement.

Interactions overview

Chitosan appears to alter the rate of absorption of water-insoluble drugs such as indometacin and griseofulvin, but it is doubtful whether this is of any clinical significance. A case report suggests that chitosan may increase the effects of warfarin, and possibly other related anticoagulants.

Chitosan + Cefalexin

The information regarding the use of chitosan with cefalexin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

There was no significant difference in the AUC and maximum levels of cefalexin 10 mg/kg given alone, and when rats were pretreated with oral chitosan 25 mg/kg.

Mechanism

Chitosan does not appear to alter the gastrointestinal absorption of water-soluble drugs such as cefalexin.

Importance and management

The evidence is limited to experimental data and the pharmaco-kinetics of cefalexin were unchanged. Therefore, no action is considered necessary.

Chitosan + Food

No interactions found.

Chitosan + Griseofulvin

The information regarding the use of chitosan with griseofulvin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

The AUCo-io and maximum levels of griseofulvin 50 mg/kg were both reduced by about two-thirds when rats were pretreated with oral chitosan 25 mg/kg. The time to reach maximum levels was also prolonged.

Mechanism

Little understood. The bioavailability of some formulations of griseofulvin are known to be enhanced when given with high-fat meals because the high levels of bile salts increase the solubilisation of this water-insoluble drug. The authors suggest that, by binding to bile acids, chitosan inhibits this effect, which in turn affects the dissolution rate and the gastrointestinal absorption of griseofulvin.This seems more likely than being due to a delay in gastric emptying, because chitosan did not alter the rate of absorption of paracetamol, below.

Importance and management

Evidence appears to be limited to the experimental study cited above, which suggests that the rate of absorption of griseofulvin is markedly reduced by chitosan. Furthermore, the extent of absorption might be reduced, although the sampling time was not long enough to conclude this. Making a clinical recommendation from these data alone is therefore difficult. It could be argued that chitosan is unlikely to affect conventional micronised formulations of griseofulvin, which are well absorbed when taken with food. Until more is known, an alternative cautious approach would be to advise patients to avoid chitosan while taking a course of griseofulvin, to minimise the risk of reduced griseofulvin efficacy.

Chitosan + Herbal medicines

No interactions found.

Chitosan + Indometacin

The information regarding the use of chitosan with indometacin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

There was no significant difference in the AUC and maximum levels of indometacin 10 mg/kg when rats were pretreated with oral chitosan 25 mg/kg, although the rate of absorption (time to reach maximum levels) was prolonged.

Mechanism

Little understood. The authors suggest that by binding to bile acids, chitosan inhibits the solubilisation and the gastrointestinal absorption of indometacin, which is not water soluble. They suggest that the effect of chitosan is not due to a delay in gastric emptying, because it did not alter the rate of absorption of paracetamol, below.

Importance and management

The evidence is limited to experimental data and the extent of indometacin absorption was unchanged. Therefore, no action is considered necessary.

Chitosan + Paracetamol (Acetaminophen)

The information regarding the use of chitosan with paracetamol is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

There was no significant difference in the AUC and maximum levels of paracetamol 30 mg/kg when rats were pretreated with oral chitosan 25 mg/kg.

Mechanism

Paracetamol absorption is dependent on the rate of gastric emptying, and it is often used to study this. The findings of this study suggest that chitosan does not alter the gastric emptying rate.

Importance and management

The evidence is limited to experimental data and the pharmacokinetics of paracetamol were unchanged. Therefore, no action is considered necessary.

Chitosan + Warfarin and related drugs

An isolated report describes an increase in the INR of an elderly man taking warfarin when he also took chitosan.

Clinical evidence

A case report describes an 83-year-old man, with type 2 diabetes, who was receiving warfarin (2.5 mg daily for one year, with an INR of between 2 and 3) for atrial fibrillation. At a routine blood test his INR was found to be about 3.7, and, although the dose of warfarin was halved, 3 days later his INR was more than 9. On discussion, it was established that he had recently started taking chitosan 1.2 g twice daily. He was advised to stop this supplement and was subsequently restablised on warfarin. About one month later, the patient restarted the chitosan, which again resulted in a raised INR.

Experimental evidence

No relevant data found.

Mechanism

Chitosan sulfate has been reported to have anticoagulant activity, but this has not been found with chitosan. The authors therefore suggest that chitosan impaired the absorption of fat-soluble vitamins, including vitamin K. Warfarin is a vitamin K antagonist and a reduction in vitamin K would be expected to enhance its effects.

Importance and management

Evidence is limited to this case, and the mechanism is largely speculative; however, an interaction seems probable. The evidence is too slim to forbid patients taking warfarin from also taking chitosan, but it would seem prudent to discuss the possible outcome and advise an increase in the frequency of anticoagulant monitoring; measuring the INR after a few days of concurrent use seems reasonable. There appears to be no evidence regarding other anticoagulants, but, if the mechanism is correct, all vitamin K antagonists (coumarins and indanediones) would be expected to be similarly affected.