Skip to main content

Advertisement

SpringerLink
Log in

Species Difference in Intestinal Absorption Mechanism of Etoposide and Digoxin between Cynomolgus Monkey and Rat

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The oral bioavailability of some therapeutic agents is markedly lower in cynomolgus monkeys than in humans. We investigated small-intestinal absorption of the P-glycoprotein (P-gp) substrates etoposide and digoxin in monkeys to clarify the influence of efflux transport on their intestinal permeability.

Methods

The pharmacokinetics of etoposide and digoxin was examined in monkeys and rats after oral and intravenous administration. Intestinal permeability and segmental differences in permeability were investigated with an Ussing-type chamber.

Results

The bioavailability of etoposide was 12.9 and 13.9% in monkeys and rats, respectively. Total body clearance of etoposide in monkeys was much less than hepatic blood flow, suggesting that the bioavailability would be limited at intestinal absorption. Marked vectorial transport of etoposide in the secretory direction was observed in rats, especially in the lower small intestine, and segmental differences were consistent with the distribution of P-gp expression. Vectorial transport was minimal in monkey small intestine. Our kinetic analysis indicated that P-gp contributes little to the intestinal permeability of etoposide and digoxin in monkeys, and apical uptake is rate-limiting.

Conclusion

Low bioavailability of etoposide in monkeys is due to poor intestinal uptake resulting from low influx from the apical side, rather than secretion via P-gp.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4A, B

Similar content being viewed by others

References

  1. K. W. Ward, R. Nagilla, and L. J. Jolivette. Comparative evaluation of oral systemic exposure of 56 xenobiotics in rat, dog, monkey and human. Xenobiotica. 35:191–210 (2005).

    Article  PubMed  CAS  Google Scholar 

  2. W. L. Chiou, and P. W. Buehler. Comparison of oral absorption and bioavailablity of drugs between monkey and human. Pharm Res. 19:868–74 (2002).

    Article  PubMed  CAS  Google Scholar 

  3. W. K. Sietsema. The absolute oral bioavailability of selected drugs. Int J Clin Pharmacol Ther Toxicol. 27:179–211 (1989).

    PubMed  CAS  Google Scholar 

  4. T. Nishimura, N. Amano, Y. Kubo, M. Ono, Y. Kato, H. Fujita, Y. Kimura, and A. Tsuji. Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey. Drug Metab Dispos. 35:1275–1284 (2007).

    Article  PubMed  CAS  Google Scholar 

  5. P. B. Watkins. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev. 27:161–170 (1997).

    Article  PubMed  CAS  Google Scholar 

  6. L. Z. Benet, C. L. Cummins, and C. Y. Wu. Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int J Pharm. 277:3–9 (2004).

    Article  PubMed  CAS  Google Scholar 

  7. M. Maliepaard, G. L. Scheffer, I. F. Faneyte, M. A. van Gastelen, A. C. Pijnenborg, A. H. Schinkel, M. J. van De Vijver, R. J. Scheper, and J. H. Schellens. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 61:3458–3464 (2001).

    PubMed  CAS  Google Scholar 

  8. A. D. Mottino, T. Hoffman, L. Jennes, and M. Vore. Expression and localization of multidrug resistant protein mrp2 in rat small intestine. J Pharmacol Exp Ther. 293:717–723 (2000).

    PubMed  CAS  Google Scholar 

  9. M. F. Fromm, H. M. Kauffmann, P. Fritz, O. Burk, H. K. Kroemer, R. W. Warzok, M. Eichelbaum, W. Siegmund, and D. Schrenk. The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol. 157:1575–1580 (2000).

    PubMed  CAS  Google Scholar 

  10. Q. Wang, R. K. Bhardwaj, D. Herrera-Ruiz, N. N. Hanna, I. T. Hanna, O. S. Gudmundsson, T. Buranachokpaisan, I. J. Hidalgo, and G. T. Knipp. Expression of multiple drug resistance conferring proteins in normal Chinese and Caucasian small and large intestinal tissue samples. Mol Pharm. 1:447–454 (2004).

    Article  PubMed  CAS  Google Scholar 

  11. T. Terao, E. Hisanaga, Y. Sai, I. Tamai, and A. Tsuji. Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier. J Pharm Pharmacol. 48:1083–1089 (1996).

    PubMed  CAS  Google Scholar 

  12. M. Takano, R. Yumoto, and T. Murakami. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther. 109:137–61 (2006).

    Article  PubMed  CAS  Google Scholar 

  13. J. D. Allen, S. C. Van Dort, M. Buitelaar, O. van Tellingen, and A. H. Schinkel. Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res. 63:1339–1344 (2003).

    PubMed  CAS  Google Scholar 

  14. V. D. Makhey, A. Guo, D. A. Norris, P. Hu, J. Yan, and P. J. Sinko. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm Res. 15:1160–1167 (1998).

    Article  PubMed  CAS  Google Scholar 

  15. J. G. Hardman, and L. E. Limbird. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. McGraw-Hill, New York, (2001).

    Google Scholar 

  16. B. Davies, and T. Morris. Physiological parameters in laboratory animals and humans. Pharm Res. 10:1093–1095 (1993).

    Article  PubMed  CAS  Google Scholar 

  17. J. C. Shah, J. R. Chen, and D. Chow. Oral bioavailability and in situ absorption of etoposide in rat. Int J Pharm. 84:223–32 (1992).

    Article  CAS  Google Scholar 

  18. R. Tian, N. Koyabu, H. Takanaga, H. Matsuo, H. Ohtani, and Y. Sawada. Effects of grapefruit juice and orange juice on the intestinal efflux of P-glycoprotein substrates. Pharm Res. 19:802–809 (2002).

    Article  PubMed  CAS  Google Scholar 

  19. A. V. Kamath, R. A. Morrison, T. W. Harper, S. J. Lan, A. M. Marino, and S. Chong. Multiple pathways are involved in the oral absorption of BMS-262084, a tryptase inhibitor, in rats: role of paracellular transport, binding to trypsin, and P-glycoprotein efflux. J Pharm Sci. 94:1115–1123 (2005).

    Article  PubMed  CAS  Google Scholar 

  20. R. H. Stephens, J. Tanianis-Hughes, N. B. Higgs, M. Humphrey, and G. Warhurst. Region-dependent modulation of intestinal permeability by drug efflux transporters: in vitro studies in mdr1a(-/-) mouse intestine. J Pharmacol Exp Ther. 303:1095–1101 (2002).

    Article  PubMed  CAS  Google Scholar 

  21. M. D. Troutman, and D. R. Thakker. Efflux ratio cannot assess P-glycoprotein-mediated attenuation of absorptive transport: asymmetric effect of P-glycoprotein on absorptive and secretory transport across Caco-2 cell monolayers. Pharm Res. 20:1200–1209 (2003).

    Article  PubMed  CAS  Google Scholar 

  22. V. J. Harvey, M. L. Slevin, S. P. Joel, A. Johnston, and P. F. Wrigley. The effect of dose on the bioavailability of oral etoposide. Cancer Chemother Pharmacol. 16:178–181 (1986).

    Article  PubMed  CAS  Google Scholar 

  23. S. Reif, M. C. Nicolson, D. Bisset, M. Reid, C. Kloft, U. Jaehde, and H. L. McLeod. Effect of grapefruit juice intake on etoposide bioavailability. Eur J Clin Pharmacol. 58:491–494 (2002).

    Article  PubMed  CAS  Google Scholar 

  24. K. R. Hande, M. G. Krozely, F. A. Greco, J. D. Hainsworth, and D. H. Johnson. Bioavailability of low-dose oral etoposide. J Clin Oncol. 11:374–377 (1993).

    PubMed  CAS  Google Scholar 

  25. D. E. Clark. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption. J Pharm Sci. 88:807–814 (1999).

    Article  PubMed  CAS  Google Scholar 

  26. C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 46:3–26 (2001).

    Article  PubMed  CAS  Google Scholar 

  27. H. M. Yao, and W. L. Chiou. The complexity of intestinal absorption and exsorption of digoxin in rats. Int J Pharm (2006).

  28. B. Noe, B. Hagenbuch, B. Stieger, and P. J. Meier. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci U S A. 94:10346–10350 (1997).

    Article  PubMed  CAS  Google Scholar 

  29. X. Cheng, J. Maher, C. Chen, and C. D. Klaassen. Tissue distribution and ontogeny of mouse organic anion transporting polypeptides (Oatps). Drug Metab Dispos. 33:1062–1073 (2005).

    Article  PubMed  CAS  Google Scholar 

  30. G. A. Kullak-Ublick, M. G. Ismair, B. Stieger, L. Landmann, R. Huber, F. Pizzagalli, K. Fattinger, P. J. Meier, and B. Hagenbuch. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 120:525–533 (2001).

    Article  PubMed  CAS  Google Scholar 

  31. Y. Su, X. Zhang, and P. J. Sinko. Human organic anion-transporting polypeptide OATP-A (SLC21A3) acts in concert with P-glycoprotein and multidrug resistance protein 2 in the vectorial transport of Saquinavir in Hep G2 cells. Mol Pharm. 1:49–56 (2004).

    Article  PubMed  CAS  Google Scholar 

  32. R. H. Stephens, C. A. O’Neill, J. Bennett, M. Humphrey, B. Henry, M. Rowland, and G. Warhurst. Resolution of P-glycoprotein and non-P-glycoprotein effects on drug permeability using intestinal tissues from mdr1a (-/-) mice. Br J Pharmacol. 135:2038–2046 (2002).

    Article  PubMed  CAS  Google Scholar 

  33. A. Guo, W. Marinaro, P. Hu, and P. J. Sinko. Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 30:457–463 (2002).

    Article  PubMed  CAS  Google Scholar 

  34. T. Takeuchi, S. Yoshitomi, T. Higuchi, K. Ikemoto, S. Niwa, T. Ebihara, M. Katoh, T. Yokoi, and S. Asahi. Establishment and characterization of the transformants stably expressing MDR1 derived from various animal species in LLC-PK(1). Pharm Res. 23:1460–1472 (2006).

    Article  PubMed  CAS  Google Scholar 

  35. N. Zelcer, T. Saeki, G. Reid, J. H. Beijnen, and P. Borst. Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 276:46400–46407 (2001).

    Article  PubMed  CAS  Google Scholar 

  36. B. D. Stride, C. E. Grant, D. W. Loe, D. R. Hipfner, S. P. Cole, and R. G. Deeley. Pharmacological characterization of the murine and human orthologs of multidrug-resistance protein in transfected human embryonic kidney cells. Mol Pharmacol. 52:344–353 (1997).

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    T. Nishimura, Y. Kato, Y. Kubo & A. Tsuji

  2. Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, Osaka, 532-8686, Japan

    N. Amano, M. Ono, Y. Kimura & H. Fujita

Authors
  1. T. Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Amano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Tsuji.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nishimura, T., Kato, Y., Amano, N. et al. Species Difference in Intestinal Absorption Mechanism of Etoposide and Digoxin between Cynomolgus Monkey and Rat. Pharm Res 25, 2467–2476 (2008). https://doi.org/10.1007/s11095-008-9658-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-008-9658-4

KEY WORDS

Search

Navigation