Comparison of the Pharmacokinetics and Pharmacodynamics of the Aldose Reductase Inhibitors, AL03152 (RS), AL03802 (R), and AL03803 (S)
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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 V ss 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.
- 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).
- 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).
- 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).
- 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.
- 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.
- 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).
- 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).
- 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).
- 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). CrossRef
- 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).
- 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).
- 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).
- 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.
- Personal communication with D. Ziegler of Clayton Foundation Biochemical Institute and Department of Chemistry and Biochemistry, University of Texas, Austin, TX 78712.
- Comparison of the Pharmacokinetics and Pharmacodynamics of the Aldose Reductase Inhibitors, AL03152 (RS), AL03802 (R), and AL03803 (S)
Volume 10, Issue 4 , pp 593-597
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- aldose reductase inhibitor
- AL03152 (RS)
- AL03802 (R)
- AL03803 (S)
- Industry Sectors
- Author Affiliations
- 1. Research and Development, Alcon Laboratories, Inc., 6201 South Freeway, Fort Worth, Texas, 76134
- 2. Department of Pharmaceutics, University of Washington, Seattle, Washington