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Multidrug Resistance Reversal Activity of Some New Dihydropyridines Studied by IN SITU Single-Pass Intestinal Perfusion (SPIP) Method in Rat

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P-glycoprotein (P-gp) mediated efflux affects the pharmacokinetics of several drugs. By analogy to verapamil, 1,4-dihydropyridines (DHPs) have been widely studied as P-gp inhibitors. Previously, we have reported on two new DHPs: IA1(A) and IIA5(B) as inhibitors of human MRP1, an efflux protein closely related to P-gp. The aim of the present study was to investigate the inhibitory effects of these two compounds on intestinal P-gp using the method of in situ single-pass intestinal perfusion (SPIP) in rat. According to this, the intestinal absorption of zidovudine (a P-gp substrate) was studied in anaesthetized rat jejunum in the absence and presence of DHPs IA1(A) and IIA5(B) (2 mg/kg). Verapamil (0.8 mg/kg), a well-known P-gp inhibitor, was employed as a standard. Zidovudine solution (200 ig/mL) in phosphate buffer (pH 7.4) was perfused through the jejunal segment, the perfusate concentrations were quantified by HPLC, and the permeability coefficient (Peff) and fraction absorbed (Fabs) were calculated. Phenol red was used as a non-absorbable marker to correct water flux through the segment. In rats pretreated with compounds IA1 and IIA5, Peff and Fabs of zidovudine were found to be 0.1669 ± 0.12 cm/sec, 0.2035 ± 0.18 and 0.2798 ± 0.12 cm/sec, 0.3015 ± 0.14, respectively, and were comparable to those of the standard (Peff = 0.462713 ± 0.3 cm/sec, Fabs = 0.511835 ± 0.14). The differences between IA1, IIA5 and the standard were evaluated using ANOVA and found to be statistically significant (P < 0.05). Compounds IA1 and IIA5 have a modulating effect on intestinal P-gp. Compound IIA5 was relatively more potent P-gp inhibitor and, quite interestingly, the results were in agreement with our earlier in silico and in vitro studies.

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References

  1. M. K. Arunasree and R. Arshad, Antimicrob. Agents Chemother., 55, 439 – 442 (2011).

    Article  Google Scholar 

  2. E. Teodori, S. Dei, C. Martelli, et al., Curr. Drug Targets, 7, 893 – 909 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. C. F. Higgins, Nature, 446, 749 – 757 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. J. P. Gillet and M. M. Gottesman, Methods Mol. Biol., 596, 47 – 76 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. T. Tsuruo, H. Iida, M. Nojiri, et al., Cancer Res., 43, 2905 – 2910 (1983).

    CAS  PubMed  Google Scholar 

  6. P. A. Philip, S. Joel, S. C. Monkman, et al., Brit. J. Cancer, 65, 267 – 270 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. A. Zarrin, A. R. Mehdipour, and R. Miri, Chem. Biol. Drug Des., 76, 369 – 381 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. H. Engi, H. Sakagami, M. Kawase, et al., In Vivo, 20, 637 – 644 (2006).

    CAS  PubMed  Google Scholar 

  9. X. F. Zhou, R. A. Coburn, and M. E. Morris, J. Pharm. Sci., 94, 2256 – 2265 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. A. Shah, J. Bariwal, J. Molnar, et al., Top. Heterocycl. Chem., 15, 201 – 252 (2008).

    CAS  Google Scholar 

  11. A. T. Fojo, K. Ueda, D. J. Slamon, et al., Proc. Natl. Acad. Sci. USA, 84, 265 – 269 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. M. V. S. Varma, M. Sarkar, et al., J. Chromatogr. B, 816, 243 – 249 (2005).

    Article  CAS  Google Scholar 

  13. S. V. Ambudkar, S. Dey, C. A. Hrycyna, et al., Annu. Rev. Pharmacol. Toxicol., 39, 361 – 398 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. R. L. Linardi and C. C. Natalini, Ciência Rural, Santa Maria, 36, 336 – 341 (2006).

    Article  CAS  Google Scholar 

  15. N. Akhtar, A. Ahad, R. K. Khar, et al., Expert Opin. Ther. Pat., 21, 561 – 576 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. T. Terao, E. Hisanaga, Y. Sai, et al., J. Pharm. Pharmacol., 48, 1083 – 1089 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. B. Greiner, M. Eichelbaum, P. Fritz, et al., J. Clin. Invest., 104, 147 – 153 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. N. Nagare, A. Damre, K. S. Singh, et al., Indian J. Pharm. Sci., 72, 625 – 629 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. L. Barthe, J. Woodley, and G. Houin, Fund. Clin. Pharmacol., 13, 154 – 168 (1999).

    Article  CAS  Google Scholar 

  20. N. Prasad, G. Dinesh, and B. Sathish Kumar, Eur. J. Pharm. Sci., 44, 27 – 31 (2011).

    Article  Google Scholar 

  21. N. F. Ho, J. Y. Park, P. F. Ni, et al., in: Animal Models for Oral Drug Delivery in Man, W. Crouthamel and A. Sarapu (eds.), Amer. Pharm. Assoc., Washington DC (1983), pp. 27 – 106.

    Google Scholar 

  22. H. H. Lu, J. Thomas, and D. Fleisher, J. Pharm. Sci., 81, 21 – 25 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. U. Fagerholm, M. Johansson, and H. Lennernas, Pharm. Res., 13, 1336 – 1342 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. B. H. Stewart, O. H. Chan, R. H. Lu, et al., Pharm. Res. 12, 693 – 699 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. K. Sirisha, M. Chandra Shekhar, K. Uma Sankar, et al., Bioorg. Med. Chem., 19, 3249 – 3254 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. H. Saitoh and B. J. Aungst, Pharm. Res., 12, 1304 – 1310 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Guidelines for Acute Oral Toxicity of Chemicals, Test No. 425 (Adopted 3 October 2008), Organization for Economic Cooperation and Development (OECD).

  28. D. Fleisher, K. C. Johnson, B. H. Stewart, et al., J. Pharm. Sci., 75, 934 – 939 (1986).

    Article  CAS  PubMed  Google Scholar 

  29. L. Salphati, K. Childers, L. Pan, et al., J. Pharm. Pharmacol., 53, 1007 – 1013 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. P. Zakeri-Milania, V. Hadi, T. Hosnieh, et al., J. Pharm. Pharmaceut. Sci., 10, 368 – 379 (2007).

    Google Scholar 

  31. N. Sunil Thomas and P. Ramesh, Eur. J. Pharm. Sci., 18, 71 – 79 (2003).

    Article  Google Scholar 

  32. R. Sandstrom and H. Lennernas, Drug Metab. Dispos., 27, 951 – 955 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to UCPSc, Kakatiya University (Warangal, TS, India) for providing the facilities. One of the authors (K. S.) is thankful to the University Grants Commission (UGC, New Delhi, India) for the award of SRF and to the management of Vaagdevi College of Pharmacy (Warangal, TS, India) for their encouragement.

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Authors and Affiliations

  1. Medicinal Chemistry and DMPK & Clinical Pharmacology Research Divisions, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana, India

    K. Sirisha, G. Achaiah, N. Prasad, S. Bhasker & L. Umachander

  2. Medicinal Chemistry Research Division, Vaagdevi College of Pharmacy, Kishanpura, Warangal, Telangana, India

    K. Sirisha

  3. R&D Centre, Symed Labs Limited, Unit-V, Phase-I, I. D. A., Jeedimetla, Hyderabad, Telangana, 500005, India

    V. Malla Reddy

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  1. K. Sirisha
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  2. G. Achaiah
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  3. N. Prasad
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  4. S. Bhasker
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  5. L. Umachander
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  6. V. Malla Reddy
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Correspondence to G. Achaiah.

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Sirisha, K., Achaiah, G., Prasad, N. et al. Multidrug Resistance Reversal Activity of Some New Dihydropyridines Studied by IN SITU Single-Pass Intestinal Perfusion (SPIP) Method in Rat. Pharm Chem J 52, 8–14 (2018). https://doi.org/10.1007/s11094-018-1757-x

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  • DOI: https://doi.org/10.1007/s11094-018-1757-x

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