Pharmaceutical Research

, Volume 10, Issue 4, pp 593–597 | Cite as

Comparison of the Pharmacokinetics and Pharmacodynamics of the Aldose Reductase Inhibitors, AL03152 (RS), AL03802 (R), and AL03803 (S)

  • Young Han Park
  • Philip R. Mayer
  • Ronnie Barker
  • Mark DuPriest
  • Brenda W. Griffin
  • Gary W. Williams
  • Billie M. York
  • John T. Slattery

Abstract

The pharmacokinetics of AL03152 (RS) and its enantiomers, AL03802 (R) and AL03803 (S), were studied in the Sprague–Dawley rat following intravenous bolus administration. The enantiomers had differing pharmacokinetic profiles, while the racemic compound exhibited pharmacokinetic parameters approximating the mean values of the individual enantiomers. The total clearance (CLT) values of the two enantiomers were similar, but the intrinsic clearance (Clint) was much greater for the S-enantiomer than for the R-enantiomer. The volume of distribution (Vss) for AL03802 (R) was threefold greater than that for AL03803 (S). The stereoselectivity in Vss could not be totally accounted for by the slight difference in serum protein binding of the isomers and resulted in a difference in the half-lives of the enantiomers. Only the R-isomer exhibited a persistent terminal elimination phase, consistent with more extensive tissue binding than the S-isomer. AL03152 enantiomers were equivalent in potency assessed from in vitro IC50 values toward rat lens aldose reductase and rat kidney L-hexonate dehydrogenase and lens EC50 values in diabetic rats.

aldose reductase inhibitor enantiomers pharmacokinetics IC50 EC50 AL03152 (RS) AL03802 (R) AL03803 (S) 

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REFERENCES

  1. 1.
    R. K. Brazzell, Y. H. Park, C. B. Wooldridge, B. McCue, R. Barker, R. Couch, and B. York. Interspecies comparison of the pharmacokinetics of aldose reductase inhibitors. Drug Metab. Disp. 18:435–440 (1990).Google Scholar
  2. 2.
    R. K. Brazzell, P. R. Mayer, R. Dobbs, P. J. McNamara, R. Teng, and J. T. Slattery. Dose-dependent pharmacokinetics of the aldose reductase inhibitor imirestat in man. Pharm. Res. 8:112–118 (1991).Google Scholar
  3. 3.
    Y. H. Park, R. Barker, B. Griffin, D. Barratt, M. DuPriest, K. Brazzell, B. York, and P. Mayer. Pharmacokinetics and efficacy of structurally related spirohydantoin and spirosuccinimide aldose reductase inhibitors. Xenobiotica 22:543–550 (1992).Google Scholar
  4. 4.
    Y. H. Park, P. Mayer, K. Brazzell, B. York, R. Barker, B. McCue, J. Mattern, B. Bracken, M. Stoltz, and R. Couch. Comparative disposition studies of the aldose reductase inhibitors imirestat and AL03152. Abstracts, Third North American ISSX Meeting, 1990, p. 18, No. 41.Google Scholar
  5. 5.
    B. W. Griffin, G. W. Williams, J. Y. Crider, R. K. Brazzell, P. R. Mayer, Y. H. Park, M. T. DuPriest, and B. M. York. Efficacy of aldose reductase inhibitors AL03152 and AL04114 administered to diabetic rats for one month. Abstracts, United States-Japan Aldose Reductase Workshop, 1991, p. 89, P38.Google Scholar
  6. 6.
    P. J. McNamara, R. A. Blouin, and R. K. Brazzell. Serum protein binding of AL01576, a new aldose reductase inhibitor. Pharm. Res. 5:319–321 (1988).Google Scholar
  7. 7.
    B. A. McCue, Y. H. Park, R. K. Brazzell, and J. J. Boltralik. Capillary gas chromatographic—electron-capture assay for the aldose reductase inhibitor imirestat in lens and plasma. J. Chromatogr. 565:255–264 (1991).Google Scholar
  8. 8.
    B. W. Griffin and L. G. McNatt. Characterization of the reduction of 3-acetylpyridine adenine dinucleotide phosphate by benzyl alcohol catalyzed by aldose reductase. Arch. Biochem. Biophys. 246:75–81 (1986).Google Scholar
  9. 9.
    B. W. Griffin, L. G. McNatt, M. L. Chandler, and B. M. York. Effects of two new aldose reductase inhibitors, AL01567 and AL01576, in diabetic rats. Metabolism 36:486–490 (1987).CrossRefPubMedGoogle Scholar
  10. 10.
    K. Yamaoka, T. Nakagawa, and T. Uno. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J. Pharmacokin. Biopharm. 6:165–175 (1978).Google Scholar
  11. 11.
    Y. H. Park, C. B. Wooldridge, J. Mattern, M. L. Stoltz, and R. K. Brazzell. Disposition of the aldose reductase inhibitor AL01576 in rats. J. Pharm. Sci. 77:110–115 (1988).Google Scholar
  12. 12.
    J. Y. Chien, C. R. Banfield, R. K. Brazzell, P. R. Mayer, and J. T. Slattery. Saturable tissue binding and imirestat pharmacokinetics in rats. Pharm. Res. 9:469–473 (1992).Google Scholar
  13. 13.
    Y. H. Park, P. R. Mayer, R. Barker, J. Mattern, B. Griffin, G. W. Williams, and B. M. York. Comparison of the pharmacokinetics and efficacy of the aldose reductase inhibitors, AL03152 (RS), AL03802 (R) and AL03803 (S). Gordon Research Conference on Drug Metabolism, 1991, Poster No. T-8.Google Scholar
  14. 14.
    Personal communication with D. Ziegler of Clayton Foundation Biochemical Institute and Department of Chemistry and Biochemistry, University of Texas, Austin, TX 78712.Google Scholar

Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Young Han Park
    • 1
  • Philip R. Mayer
    • 1
  • Ronnie Barker
    • 1
  • Mark DuPriest
    • 1
  • Brenda W. Griffin
    • 1
  • Gary W. Williams
    • 1
  • Billie M. York
    • 1
  • John T. Slattery
    • 2
  1. 1.Research and DevelopmentAlcon Laboratories, Inc.Fort Worth
  2. 2.Department of PharmaceuticsUniversity of WashingtonSeattle

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