sorbinil and Drug-Hypersensitivity

Neuropathy and retinopathy are two potentially serious late complications of diabetes. There is accumulating evidence that the development of these conditions is closely related to increased activity of the polyol pathway, which occurs in certain tissues as a consequence of long term hyperglycaemia. Symptomatic diabetic neuropathy may appear as one of many forms and is frequently accompanied by pain. Diabetic retinopathy is a progressive degeneration of the retina that represents one of the major causes of blindness in the developed world. A good prognosis for either of these conditions is believed to rely on early diagnosis and optimisation of glycaemic control as they become less reversible with progression of cellular damage. A new approach to the treatment of these and other late complications of diabetes may be offered by recently developed drugs, such as sorbinil, that inhibit the enzyme aldose reductase. In various animal models of late complications of diabetes sorbinil and other aldose reductase inhibitors have been shown to reverse some of the biochemical and physiological changes believed to underlie these complications. These include prevention or reversal of the accumulation of sorbitol and depletion of myo-inositol in nerve, lens and renal glomeruli. Sorbinil also counteracts the slowing of nerve conduction velocities, reverses the structural changes of Sipple stages I and II cataracts and prevents proteinuria in diabetic rats. Orally administered sorbinil is absorbed rapidly and reaches steady state plasma concentrations after 6 to 10 days' administration. Its elimination half-life is long (38-52 hours) and much greater than that of another aldose reductase inhibitor, tolrestat (10-12 hours). Within the dose range 50-250 mg about one-third of administered sorbinil appears in the urine as unchanged drug. In the small number of clinical studies of diabetic patients with neuropathies sorbinil has demonstrated limited therapeutic effects. There is now a requirement for studies of its prophylactic use and its therapeutic use in patients with diabetic neuropathy in the early stages of development.

Topics: Aldehyde Reductase; Diabetic Neuropathies; Diabetic Retinopathy; Drug Hypersensitivity; Humans; Imidazoles; Imidazolidines; Kinetics; Sugar Alcohol Dehydrogenases

Extensive animal data now exist to indicate potential benefit of sorbinil in the treatment of the major complications of diabetes mellitus. A clinical programme has been constructed to explore this therapeutic potential and encouraging evidence of drug effect has already been observed in patients with neuropathy and retinopathy. Two small preliminary studies in patients with painful neuropathy have shown that clinically significant reduction of pain was more frequently achieved with sorbinil than with placebo. A 6-month study of patients with retinopathy, using vitreous fluorophotometry as the criterion of retinal damage, showed significant (p = 0.03) benefit for the sorbinil group compared with the placebo group. Drug evaluation in these areas is complex and difficult but it is anticipated that the accumulation of additional data will further substantiate the efficacy suggested by these early findings. The only clinically important adverse effect of sorbinil is the hypersensitivity reaction. This usually occurs during the initial weeks of therapy and is similar to that seen with phenytoin. The long term use of sorbinil is without significant adverse effects.

Topics: Aldehyde Reductase; Animals; Diabetic Neuropathies; Diabetic Retinopathy; Drug Hypersensitivity; Electrophysiology; Humans; Imidazoles; Imidazolidines; Sugar Alcohol Dehydrogenases

Sorbinil is a hydantoin aldose reductase inhibitor that has shown promise as therapy for patients with diabetic complications such as neuropathy and retinopathy. However, as many as 10% of patients receiving sorbinil have had adverse reactions characterized by fever, skin rash, and myalgia. Our previous studies of phenytoin suggested that susceptibility to reactions might result from an inherited detoxification defect. We did the current study to determine if sorbinil is metabolized to reactive intermediates and if cells from patients with a history of a reaction to sorbinil are appropriate for the in-vitro investigation of susceptibility. Microsome-generated metabolites of sorbinil (50 microM) were toxic to normal peripheral blood lymphocytes (7.9% +/- 0.3% dead cells [mean +/- SE]). Toxicity was increased in the presence of an epoxide hydrolase inhibitor (17.5% +/- 0.3% dead cells) and abolished by an inhibitor of cytochrome P-450. In contrast to cells from healthy controls and diabetics who tolerated sorbinil (7.9% +/- 0.7% and 7.8% +/- 0.4% dead cells, respectively), cells from the six patients who had sorbinil reactions showed significantly increased toxicity from metabolites of sorbinil and phenytoin (19.7% +/- 2.3% dead cells, P less than 0.001). Cells from three patients who had reactions to phenytoin were similarly sensitive to sorbinil metabolites (23.4% +/- 0.3% dead cells). We conclude that sorbinil is oxidatively metabolized to a potentially toxic intermediate. Certain patients may be at increased risk for developing hypersensitivity reactions. Development of this important new drug has been hampered by uncommon but potentially severe reactions. An increased understanding of the steps involved in the development of adverse reactions could lead to screening tests or to the development of safer compounds.

Topics: Adult; Animals; Biotransformation; Diabetes Mellitus; Drug Hypersensitivity; Female; Humans; Imidazoles; Imidazolidines; In Vitro Techniques; Lymphocytes; Male; Mice; Microsomes, Liver; Middle Aged; Phenytoin