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Uptake Is the Rate-limiting Step in the Overall Hepatic Elimination of Pravastatin at Steady-state in Rats

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Abstract

Purpose. Of the HMG-CoA reductase inhibitors, the hydrophilic pravastatin has been shown to exhibit relatively specific inhibition of cholesterol synthesis in the liver. As one of the reasons for this relatively specific pharmacological activity, we demonstrated that the tissue distribution of pravastatin is limited because of its high hydrophilicity, while hepatic uptake by active transport takes place at the liver surface via a multispecific anion transporter (M. Yamazaki et al., Am. J. Physiol., 264, G36-44, 1993). In this study, we examined the hepatic elimination of pravastatin at steady-state.

Methods. After i.v. infusion, the plasma concentrations of pravastatin in both arterial and hepatic venous blood were measured.

Results. The hepatic availability at steady-state exhibited a clear increase on increasing the infusion rate of pravastatin. The total hepatic elimination rate at steady-state exhibited Michaelis-Menten type saturation with the drug concentration in the capillary defined by typical mathematical models (i.e., well-stirred, parallel-tube and dispersion models), Km and Vmax values being comparable with those obtained from analysis of the initial uptake velocity using in vitro isolated hepatocytes.

Conclusions. These results indicate that overall hepatic intrinsic clearance of pravastatin at steady-state is regulated by the uptake process, followed by rapid metabolism and/or biliary excretion with minimal efflux to the circulating blood.

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REFERENCES

  1. M. Yamazaki, T. Tokui, M. Ishigami, and Y. Sugiyama, Biopharm. Drug Dispoit., in press

  2. P. J. Meier, Seminars in Liver Disease, 8:293–307, (1988).

    Google Scholar 

  3. M. Yamazaki, H. Suzuki, M. Hanano, T. Tokui, T. Komai, and Y. Sugiyama, Am. J. Physiol., 264:G36–G44, (1993).

    Google Scholar 

  4. K. Ziegler, and W. Stunkel, Biochim. Biophys. Acta. 1139:203–209, (1992).

    Google Scholar 

  5. M. Ishigami, T. Tokui, T. Komai, K. Tsukahara, M. Yamazaki, and Y. Sugiyama; Pharm. Res., 12:1741–1745, (1995).

    Google Scholar 

  6. K. S. Pang, and M. Rowland, I: J. Pharmacokin. Biopharm., 5:625–653, (1977).

    Google Scholar 

  7. K. Winkler, S. Keiding, and N. Trgstrup, ed. by G. Paumgartner and R. Preisig. Basel, Karger, 1973, 144–155.

  8. M. S. Roberts, and M. Rowland, J. Pharmacokin. Biopharm., 14:261–288 (1986).

    Google Scholar 

  9. M. Yokota, T. Iga, S. Awazu, and M. Hanano. J. Appl. Physiol. 4:349–441, (1976).

    Google Scholar 

  10. S. Muramatsu, K. Miyaguchi, H. Iwabuchi, Y. Matsushita, T. Nakamura, T. Kinoshita, M. Tanaka, and H. Takahagi, XENOBI-OTICA, 22:487–498 (1992).

    Google Scholar 

  11. R. J. Dedrick, D. S. Zaharko, and R. Lutz, J. Pharm. Sci., 62:662–690, (1973).

    Google Scholar 

  12. K. Yamaoka, Y. Tanigawara, Y. Nakagawa and T. Uno. J. Pharmacobio-Dyn., 4:879–885, (1981).

    Google Scholar 

  13. K. Yamaoka, T. Nakazawa, and T. Uno, J. Pharmacokin. Biopharm., 6:165–175, (1978).

    Google Scholar 

  14. T. Komai, K. Kawai, T. Tokui, Y. Tokui, C. Kuroiwa, E. Shigehara and M. Tanaka, Eur. J. Drug Met. Pharmacokin. 17:103–113, (1992).

    Google Scholar 

  15. Y. Tsujita, and Y. Watanabe, Cardiovasc. Drug Rev., 7:110–126, (1989).

    Google Scholar 

  16. M. Rowland, L. Z. Benet, and G. G. Graham, J. Pharmacokin. Biopharm., 1:123–136, (1973).

    Google Scholar 

  17. G. R. Wilkinson, and D. G. Shand, Clin. Pharmacol. Ther., 18:377–390, (1975).

    Google Scholar 

  18. S. Miyauchi, Y. Sugiyama, Y. Sawada, K. Morita, T. Iga, and M. Hanano, J. Pharmacokin. Biopharm., 15:25–38, (1987).

    Google Scholar 

  19. S. Miyauchi, Y. Sawada, T. Iga, M. Hanano, and Y. Sugiyama, Biol. Pharm. Bull., 16:1019–1024 (1993).

    Google Scholar 

  20. M. Yamazaki, H. Suzuki and Y. Sugiyama, Pharm. Res., 13:497–513, (1996).

    Google Scholar 

  21. M. Yamazaki, K. Kobayashi and Y. Sugiyama, in Biopharm. Drug Disposit., in press.

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Yamazaki, M., Akiyama, S., Nishigaki, R. et al. Uptake Is the Rate-limiting Step in the Overall Hepatic Elimination of Pravastatin at Steady-state in Rats. Pharm Res 13, 1559–1564 (1996). https://doi.org/10.1023/A:1016044032571

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  • DOI: https://doi.org/10.1023/A:1016044032571

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