A Novel Method for the Study of P-glycoprotein Inhibition

A novel method for the study of p-glycoprotein inhibition by in situ  cancerous colon perfusion in rats

Abstract:

Studies on  p-glycoprotein were carried out worldwide by using different cell lines like Caco2, MDR1-LLC-PK1 and MDR1-MDCK in vitro,  but most of the results were not 100% correlated with  in vivo results on p-gp functions.In situ studies are more correlated with the in  vivo studies. For the first time in the world the cancerous colon perfusion in rats is carried out in this study todetermine the permeability of the irinotecan, under the influence of p-gp modulators like verapamil and curcumin.

Methods: Single pass cancerous whole length of the colon perfusion in  rats is used. The rats were devided in to 5 groups (n=6), Group I served as control without cancer and perfused with 30μg/ml of irinotecan, propronolol and phenol red. Group II served as cancerous rats by  N-methyl N-nitroso urea. Group III,  perfused with irinotican in cancerous rats. Group IV,  perfused with irinotican, in presence of verapamil and group V pretreated with curcumin and then perfused with irinotican. The stability of irinotecan and propranolol were properly tested, and there was no sign of degradation of drugs and no sign of interaction of drugs with phenol red.

Results: HPLC-UV method found to be simple, specific, accurate, and precise. Effective permeability coefficient of irinotecan  is  0.00006 cm/s and is increased to 0.00066 cm/s a 11 fold increase in verapamil coperfused group, and 0.00006 cm/s to 0.00042 cm/s a 7 fold increase in case of curcumin pretreated group, all the results were statistically significant.

Conclusions:Cancerous colonicin situ intestinal perfusion method was successfully applied as a new method to study the permeability of irinotecan.  In situ model the results may correlate 100% with in vivo results. P-gp inhibitory activity by verapamil and curcumin found to significantly enhance the cancerous colon permeability of irinotecan. Any suitable p-gp inhibitors along with irinotecan will enhance the therapeutic benefit in the treatment of the colon cancer.

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Host:

Dr. Neerati Prasad, M.Pharm., PhD.
Assistant Professor of Pharmacy
University College of Pharmaceutical Sciences, Kak