Drug resistance places serious limitations on the efficacy of anti-cancer treatments. This phenomenon is due in part to active efflux transporters such as p-glycoprotein. More recently, data has suggested that p-glycoprotein is also involved in the passage of molecules across the blood brain barrier and in the survival of inflammatory cells. The development of substrates or inhibitors of this protein therefore represents an active area of the pharmaceutical industry. Indeed over 15 molecules are in development, over half of which are in preclinical phases of evaluation.

P-glycoprotein has also been related to the resistance of the intestinal epithelium to injury. This is of considerable interest, especially with respect to the treatment of inflammatory bowel disease (IBD).

IBD is an umbrella term used to describe two distinct clinical conditions, ulcerative colitis and Crohn's disease, both of which are chronic digestive diseases resulting from an abnormal immune system response to stimuli in the digestive tract. In 2001, the number of prevalent cases of IBD was been estimated to have totaled over 1.5 million in the major pharmaceutical markets. Currently in excess of $0.5 billion, IBD related sales have been forcasted to increase by 3-10% each year for the next 5 years. Current treatment options are sub-optimal and the present focus is on the identification of inflammatory mediators involved in IBD. A greater understanding of inflammatory pathways and new "biologic agents" that will emerge from this knowledge will expand the IBD market and provide improved options for the patient.

Japanese researchers have recently examined the role of p-glycoprotein in IBD in greater detail using the dextran sodium sulfate model of murine colitis. This model is characterized by severe inflammation in the large intestine and as shown by these researchers the expression of the the pregnane X receptor (PXR) which is involved in transcriptional regulation of p-glycoprotein as well as p-glycoprotein function. These changes occurred before severe symptoms appeared suggesting that p-glycoprotein expression may be related to the pathology of colitis. These findings are consistent with earlier data showing that inflammatory cytokines can reduce p-glycoprotein expression and that mice deficient in the p-glycoprotein gene develop spontaneous colitis.

Greater understanding of the relationship between inflammation and p-glycoprotein expression may lead to improved treatments of conditions such as IBD. On the other hand these data may also contribute to the improvement of anti-cancer p-glycoprotein blockers by facilitating the limitation of adverse effects relating to intestinal damage.

Entry date Friday, April 11, 2003

Adapted from Iizasa et al, J Pharm Sci 2003 Mar;92(3):569-76 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk