Skip to main content
Log in

Extensive Biliary Excretion of the Model Opioid Peptide [D-PEN2,5] Enkephalin in Rats

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. This study was designed to test the hypothesis that the enzymatically stable opioid peptide, [D-pen2,5] enkephalin (DPDPE), is excreted extensively into bile.

Methods. Following an i.v. bolus dose of DPDPE (10 mg/kg) to rats, concentrations of DPDPE in serum, bile, liver homogenate and urine were measured by a novel capillary zone electrophoresis method. Data were analyzed to recover the fundamental pharmacokinetic parameters (volumes of distribution; distribution and elimination rate constants governing DPDPE systemic and biliary disposition). Parallel in vitro experiments were performed to evaluate the partitioning of DPDPE between erythrocytes and plasma, as well as to assess the degree of binding of DPDPE to serum proteins.

Results. The majority of the administered dose (~80%) was recovered from bile as intact peptide. DPDPE disposition was best described by a two-compartment model with Michaelis-Menten elimination (Km: 37.5 ± 11 μg/ml; Vmax: 1143 ± 368 μg/min/kg) from the central compartment into bile, suggestive of an active hepatic transport system. DPDPE was associated with a distributional space of 486 ± 62 ml/kg. In vitro incubation of DPDPE with whole blood showed that ~65% of the peptide was associated with erythrocytes. The difference between concentrations of DPDPE in erythrocytes and plasma was statistically significant (29.2 ± 4.9 vs. 18.1 ± 3.1 μg/ml, p < 0.05), but not between whole blood and plasma (21.3 ± 2.8 vs. 18.1 ± 3.1 μg/ml, p > 0.05). Concentration-independent binding of DPDPE to serum proteins was evidenced between 10 and 100 (μg/ml, with an unbound fraction of 0.517 ± 0.182.

Conclusions. DPDPE undergoes extensive biliary excretion after i.v administration in rats. The apparent nonlinearity in the biliary excretion of DPDPE revealed by the pharmacokinetic modeling strongly suggests the existence of an active transport system(s) in hepatocytes which may mediate the rapid disappearance of DPDPE from the systemic circulation.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. W. A. Banks. Proc. Natl. Acad. Sci. U.S.A. 87:6762–6766 (1990).

    Google Scholar 

  2. W. Bouer, W. Briner, W. Doepfner, R. Haller, R. Huguenin, P. Marbach, T. J. Petcher, and J. Pless. Life Sci. 31:1133–1140 (1982).

    Google Scholar 

  3. B. D. Khan, C. T. Van Buren, S. M. Flechner, W. D. Payne, M. Boileau, and R. H. Kerman. Transplant. Proc. 15:2469–2487 (1983).

    Google Scholar 

  4. C. E. Peters. Reg. Pept. 3:361–369 (1982).

    Google Scholar 

  5. M. Sheppard, B. Shapiro, B. Pimstone, S. Kronheim, B. Berelowite, and M. Gregory. J. Clin. Endocrinol. Metab. 48:50–53 (1979).

    Google Scholar 

  6. S. Muller and G. Hochhaus. Pharm. Res. 12:1165–1170 (1995).

    Google Scholar 

  7. R. Albert, P. Marbach, W. Bauer, U. Briner, G. Fricker, and J. Pless. Life Sci. 25:517–525 (1993).

    Google Scholar 

  8. J. C. Greenfield, K. J. Cook, and I. A. Oleary. Drug Metab. Dispos. 17:518–525 (1989).

    Google Scholar 

  9. K. Ziegler, M. Frimmer, H. Kessler, I. Damm, V. Eiermann, S. Koll, and J. Zarbock. Biochim. Biophys. Acta 845:86–93 (1985).

    Google Scholar 

  10. K. Ziegler, W. Lins, and M. Frimmer. Biochim. Biophys. Acta 1061:287–296 (1991).

    Google Scholar 

  11. H. I. Mosberg, R. Hurst, V. J. Hruby, K. Gee, H. I. Yamamura, J. J. Galligan, and T. F. Burks. Proc. Natl. Acad. Sci. U.S.A. 80:5871–5874 (1983).

    Google Scholar 

  12. S. J. Weber, D. L. Greene, S. D. Sharma, H. I. Yamamura, T. H. Kramer, T. F. Burks, V. J. Hruby, L. B. Hersh, and T. P. Davis. J. Pharmacol. Exp. Ther. 259:1109–1117 (1991).

    Google Scholar 

  13. S. J. Weber, D. L. Greene, V. J. Hruby, H. I. Yamamura, F. Porreca, and T. P. Davis. J. Pharmacol. Exp. Ther. 263:1308–1316 (1992).

    Google Scholar 

  14. L. B. Hersh. J. Neurochem. 43:487–493 (1984).

    Google Scholar 

  15. C. Chen and G. M. Pollack. J. Chromatogr. B 681:363–373 (1996).

    Google Scholar 

  16. D. M. C. Ouellet and G. M. Pollack. Drug Metab. Dispos. 23:478–484 (1995).

    Google Scholar 

  17. M. Lemaire, M. Azria, R. Dannecker, P. Marbach, A. Schweitzer, and G. Maurer. Drug Metab. Dispos. 17:699–703 (1989).

    Google Scholar 

  18. T. Terasaki, H. Mizuguchi, C. Itoho, I. Tamai, M. Lemaire, and A. Tsuji. Pharm. Res. 12:12–17 (1995).

    Google Scholar 

  19. T. Nakamura, A. Hisaka, Y. Sawasaki, Y. Suzuki, T. Fukami, K. Ishikawa, M. Yano and Y. Sugiyama. J. Pharmacol. Exp. Ther. 278:564–278 (1996).

    Google Scholar 

  20. A. Lindholm. Ther. Drug Monit. 13:465–477 (1991).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, C., Pollack, G.M. Extensive Biliary Excretion of the Model Opioid Peptide [D-PEN2,5] Enkephalin in Rats. Pharm Res 14, 345–350 (1997). https://doi.org/10.1023/A:1012054222845

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1012054222845

Navigation