Tolrestat - An Aldose reductase inhibitor- Investigational drug
Drug Name:Tolrestat - An Aldose reductase inhibitor- Investigational drug
List Of Brands:
Indication Type Description:
Drug Interaction
Adverse Reaction
Pharmacology/ Pharmacokinetics
Drug Interaction:
Diabetic neuropathy
Diabetic retinopathy
Summary-
Published data although scant, suggest that tolrestat is safe and well tolerated. The ability of
aldose reductose inhibition to decrease RBC sorbitol accumulation has been demonstrated
in humans. Despite evidence for a favorable biochemical effect supporting evidence for a
beneficial clinical effect (ie prevention of late complications of diabetes) has yet to be
conclusively established.
Furthermore, the groups likely to benefit from this form of therapy, those with poor glycemic
control or long standing diabetes, present methodologic problems for assessing the cause
and effect relationship with any form of therapy
The NDA for tolrestat was filed on April 4, 1986, for diabetic neuropathy. It is phase III trials
for diabetic retinopathy . Tolrestat will be marketed as Alredase by Wyeth- Ayerst
Adverse Reaction:
Side effects-
The most common side effect reported by the manufacturer in unpublished clinical rials was
dizziness, which occurred in 11%of patients receiving 200mg tolrestat daily.
Other adverse effects that have occurred include skin rash and liver enzyme elevations.
A clear cause-effect relationship between tolrestat therapy and these adverse effects
have not been established
Pharmacology/ Pharmacokinetics:
Pharmacology-
Tolrestat , a carboxylic acid, is a aldose reductase inhibitor currently undergoing clinical trials to assess its value in controlling the biochemical abnormalities responsible for the late complications of diabetes(eg. diabetic neuropathy, and retinopathy)
Diabetic neuropathy, characterized by postural hypotension, diarrhea, pain and tingling in
muscle groups, impotence, etc occurs in about 10% of the diabetic patients with glycemic
controal and in about 70% of the patients with poorly controlled diabetes.
These late complications of insulin-dependent diabetes appear to be related to accumulation of intracellular sorbitol and galactrol which results in cellular damage. A defecit of myo-inositol may also be involved, especially in diabetic neuropathy.
Aldose reductaseis the first enzyme in the sorbitol(plyol) patway. This pathway is responsible for conversion of glucose to sorbitol and of galactose to galactitol.Under conditions of hyperglycemia, sorbitol accumulation occurs. By inhibiting aldose reductase tolrestat prevents the accumulation of ntracellular sorbitol.
Pharmacokinetics-
Tolrestat is almost completely absorbed after oral admin in healthy subjects.Bioavailability
is reduced in diabetic patients but the results are statistically significant
Peak plasma concentrations are acheived in 1 to 3 hours. Maximum decreases in red blood
cell (RBC) sorbitol occur after 3 days of treatment with 100mg twice daily. The distribution half-life averages 2 to 3 hours, whereas the elimination hal-life averages 10 to 13 hours.
Protein binding is extensive (99.5% )
Metabolism of tolrestat is minimal. The excretion is primarily by through the kidneys as
unchanged drug. The need for dosage reductions in patients with cmpramised renal function has not been established.
Clinical trials-
The majority of published data on tolrestat involves animal or invitro studies. However,
a study of 23 diabetic patients receiving tolrestat 25 to 100mg twice daily showed a dose
dependent reduction of RBC sorbitol levels of 21% and 57% repectively.
In two unpublished clinical efficacy trials, tolrestat was administered to patients with diabetic
neuropathy in a randomised, double-blind placebo controlled fashion. The short term (8 week trial) in 260 patients compared placebo to 200mg twice daily or 400mg once daily,the long term ( 1 year ) trial in patients in 548 patients compared placebo to 50, 100 or 200mg once daily or 100mg twice daily.
Compared with placebo 28% of the patients in the long term study receiving tolrestat
200mg once daily showed improvement of nerve conduction velocity and parathesis but
not pain.
Improvement was seen in both trials with a once-daily dose of 200 or 400mg. but not when
the same dose was given twice daily.
