Comparison of the pharmacokinetics and pharmacodynamics of the aldose reductase inhibitors, AL03152 (RS), AL03802 (R), and AL03803 (S).
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 (Cl(int)) 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.
Park
Y H
YH
Research and Development, Alcon Laboratories, Inc., Forth Worth, Texas 76134.
Mayer
P R
PR
Barker
R
R
DuPriest
M
M
Griffin
B W
BW
Williams
G W
GW
York
B M
BM
Slattery
J T
JT
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000037:antagonists & inhibitors; D002849:Chromatography, Gas; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006827:Hydantoins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000378:metabolism; D013237:Stereoisomerism
D005449:Fluorenes; D006827:Hydantoins; C076003:AL 3152; D013012:Sorbitol; D002237:Carbohydrate Dehydrogenases; C020590:L-glucuronate reductase; D000449:Aldehyde Reductase