| Reference | 1. Metabolism. 1989 Aug;38(8):801-4.
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Inhibition of erythrocyte anion exchange by tolrestat, an inhibitor of aldose
reductase.
<br>
Gunn RB(1), Gunn HB.
<br>
Author information: <br>
(1)Department of Physiology, Emory University School of Medicine, Atlanta 30322.
<br>
Tolrestat, and aldose-reductase inhibitor, was shown to be a rapid and potent
inhibitor of chloride exchange on the band 3 protein of human erythrocytes.
Tolrestat binds to a site distinct from the chloride transport site and binds to
one half of the transporters at 5 x 10(-7) mol/L in the absence of chloride and
at 3.6 x 10(-5) mol/L in physiologic chloride concentrations. Although these
concentrations are 20- to 1,000-fold greater than the IC50 for aldose-reductase
inhibition by tolrestat, they are achieved during routine pharmacologic therapy
in humans. Consequently, Cl/HCO3 exchange rates may be reduced and there may be
decreased CO2 clearance from coronary and respiratory center capillary beds and
inappropriate hyperpnea. There also may be transitory intracellular
alkalinization in cells with a Cl/HCO3 exchanger in their plasma membrane.
<br>
2. Clin Pharmacol Ther. 1985 Dec;38(6):625-30.
<br>
Effect of tolrestat on red blood cell sorbitol levels in patients with diabetes.
<br>
Raskin P, Rosenstock J, Challis P, Ryder S, Mullane JF, Gonzalez R, Hicks D,
Smith T, Dvornik D.
<br>
The effect of the aldose reductase inhibitor, tolrestat, on red blood cell (RBC)
sorbitol levels was studied in 23 patients with diabetes after oral dosing with
tolrestat, 25 or 100 mg b.i.d. The mean (+/- SE) RBC sorbitol levels (measured 12
hours after the preceding dose) after 3, 7, and 13 days of dosing decreased after
both dose levels. After 25 mg tolrestat the RBC sorbitol levels fell from 25.1
+/- 4.0 to 20.0 +/- 5.7 nmol/gm hemoglobin (21%) and after 100 mg tolrestat the
level fell from 26.7 +/- 3.7 to 11.4 +/- 1.7 nmol/gm hemoglobin (57%; P less than
0.001). This latter RBC sorbitol concentration is similar to levels in
individuals without diabetes. At both dosage levels the maximum decrease in RBC
sorbitol levels occurred after only 3 days of dosing. Tolrestat had no effect on
plasma glucose or hemoglobin A1 concentrations. The overall mean plasma unbound
drug concentration measured 12 hours after 100 mg tolrestat (11.7 +/- 3.0 ng/ml;
3.3 X 10(-8) mol/L) was similar to the median inhibitory level (3 X 10(-8) mol/L)
of tolrestat for sorbitol accumulation in human RBCs incubated in a high-glucose
medium. Our results demonstrate the systemic bioavailability of tolrestat and its
aldose reductase inhibitory activity in erythrocytes of patients with diabetes.
<br>
3. Ther Drug Monit. 1984;6(3):328-33.
<br>
Determination of tolrestat, a novel aldose reductase inhibitor, in serum and
tissues.
<br>
Hicks DR, Kraml M.
<br>
An ultraviolet spectrophotometric method and a high-performance liquid
chromatographic (HPLC) method were developed for the determination of tolrestat,
a novel aldose reductase inhibitor, in serum. The limits of detection of the
methods are 15 micrograms/ml and 0.2 microgram/ml, respectively. With human
serum, a modification of the HPLC method provides sensitivity to 25 ng/ml. The
specificity of the methods were compared. The HPLC method can be applied to the
lens and the sciatic nerve.
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