Z Gastroenterol 2005; 43 - 53
DOI: 10.1055/s-2005-869700

Therapeutic implications of screening MDR1/MRP1 activity in peripheral lymphocytes in inflammatory bowel disease

K Illés 3, E Schäfer 3, T Micsik 1, O Szokolóczi 1, B Bránné Németh 1, A Gelley 4, R Vernes 1, T Gyökeres 3, Á Pap 3, I Peták 2, R Schwab 1
  • 1Rational Drug Design Labs CRC
  • 21st Inst. Pathol. and Exp. Cancer Research
  • 3Dept. gastroenetrol. MÁV Hospital
  • 4POlyclinic Hosp. Brothers of St. John of God, Budapest

Aims: Most current drugs to treat inflammatory bowel disease (IBD) including corticosteroids, azathioprine, cyclosporine are substrates of ABC-MDR transporters. These proteins significantly alter intracellular drug availability and thus efficacy. Our aim was to retrospectively assess therapeutic responsiveness of relapsing CD/UC to the applied steroid/AZA doses in view of the patient's MDR profile.

Patients & Methods: 50 patients were included in the study: 35 pts had Crohn's disease and 15 pts had ulcerative colitis. 24% of pts were non-responsive to conventional pharmacotherapy, 22% of them were currently on steroids. 33% were in remission with steroids at the time of testing. Functional MDR assays were performed based on the Calcein-AM method. Lymphocytes were labeled by anti-human CD3, CD4, CD8, CD19, CD45 and monocytes by anti-human CD14 antibodies. In all cases MDR1 and MRP1 activity was assessed as described in the original assay (http://www.solvobiotech.com).

Results: MRP1 activity in CD8 lymphocyte subpopulation was decreased in patients treated with only 5-ASA, without previous history of steroids or steroid/AZA therapy (MAF MRP1=17 vs.24,5 vs.19,1, MAF Total=17 vs. 34,9 vs. 34,2). Interesetingly, MRP1 activity on CD8 positive (cytotoxic) cells was within normal limits in patients with active CD (mean MAF MRP1=16,6), compared to patients with active UC with elevated values (mean MAF MRP1=24,43).

Conclusion: ABC-MDR transporter activity is significantly elevated after steroid/AZA therapy. It is of debate, whether or not this phenomenon is related to induced expression or more active disease. Interestingly, active CD was characterized by normal CD8/MRP1 activity in contrast to UC. However, total ABC-MDR activity was high in both subsets of patients. Based on our pilot results, screening MDR activity is only warranted in relapsing disease of Ulcerative Colitis patients. Cases of high MDR activity may need a more aggressive early approach. Further prospective studies are needed.