Determination of AL01576 Concentration in Rat Lenses and Plasma by Bioassay for Aldose Reductase Activity Measurements

Abstract

Investigations on the disposition of the highly effective aldose reductase inhibitor ALO 1576 were carried out in pigmented rats after oral dosing and topical administration of a 0.1 % ophthalmic suspension by means of an assay modified from a previously described method measuring aldose reductase activity. The crude enzyme extract of pig lenses was used as a test system. From the activity remaining after addition of the plasma or lens extracts, the concentration could be determined since the inhibition constant (IC₅₀) of ALO 1576 is known. With this procedure, the concentration of AL01576 in plasma and lenses of Brown-Norway rats given different doses of the drug for 42 consecutive days were determined and compared with a gas chromatographic assay technique. These data indicate that ALO 1576 is absorbed into the lens with a substantial portion redistributing into the lens following systemic delivery. Drug concentrations were correlated with efficacy measurements, though they were lower in an animal group treated with naphthalene to provoke cataract formation. In a second animal series with Brown-Norway rats over 5 days, ALO 1576 was administered three times per day to the right eye only. During the washout period, ALO 1576 had a long persistence in plasma and lenses following this short-term topical ocular administration.

RETRACTED: Synthesis and biological evaluation of [1,2,4]triazino[4,3-a] benzimidazole acetic acid derivatives as selective aldose reductase inhibitors

“…Primary in vitro screening was conducted on a water-soluble enzymatic extract purified from rat lenses [21][22][23][24]. IC 50 values were determined by linear regression analysis of the log of the concentration-response curve.…”

Novel, Highly Potent Aldose Reductase Inhibitors: Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic Acid Derivatives

“…Primary in vitro screening was performed on a water-soluble crude enzymatic extract of rat lenses. [22][23][24][25] IC 50 values were determined by using linear regression analysis of the log concentration-response curve. Sorbinil, 26 tolrestat, 27,28 and quercetin 29 were used as the reference standards.…”

“…The diastereomeric mixtures of the target compounds 39 − 57 were used as such to evaluate their in vitro inhibitory activity against ALR2. Primary in vitro screening was performed on a water-soluble crude enzymatic extract of rat lenses. − IC 50 values were determined by using linear regression analysis of the log concentration−response curve. Sorbinil, tolrestat, , and quercetin were used as the reference standards.…”

[1,2,4]Triazino[4,3-a]benzimidazole Acetic Acid Derivatives: A New Class of Selective Aldose Reductase Inhibitors

“…Compounds 1 − 25 were evaluated for their in vitro inhibitory activity against ALR2 as well as against ALR1, SD, and GR. Primary in vitro screening was conducted on a water-soluble enzymatic extract purified from rat lenses. − IC 50 values were determined by linear regression analysis of the log of the concentration−response curve. Compounds 1 − 25 were also assayed for their ability to inhibit SD and two other enzymes not involved in the polyol pathway, namely, ALR1 and GR .…”