Aldose Reductase Inhibitors as New Antidiabetic Drugs

1 Chemistry 171

2 Functions of Aldose Reductase 172

2.1 Biochemistry of Aldose Reductase 172

2.2 Aldose Reductase-related Complications 173

3 Action of Aldose Reductase Inhibitors 173

3.1 Action on Neural Tissue 173

3.2 Action on Retina 174

3.3 Action of Kidney 174

4 Pharmacokinetics 175

4.1 Absorption 175

4.2 Plasma Levels 175

4.3 Distribution 175

4.4 Half-Life 175

4.5 Elimination 176

5 Pathological Changes in the Pharmacokinetics 176

6 Toxic and Side Effects 176

7 Interaction with Other Drugs 177

8 Clinical Trials 177

8.1 Introduction 177

8.2 Effect on Neuropathy 177

8.3 Effect on Diabetic Retinopathy 177

8.4 Effect on Diabetic Nephropathy 178

Increased aldose reductase activity is observed in tissues which are affected by complications of diabetes mellitus. The possible participation of the polyol pathway in the pathogenesis of these complications led to detailed evaluation of the role of this system both to improve the understanding of diabetes mellitus and to open up new therapeutic possibilities in the prevention of complications. The underlying therapeutic idea is to prevent lesions caused by high glucose concentrations. This seems to be possible for those tissues with insulin-independent glucose uptake and high activity of the polyol pathways (for a detailed review on aldose reductase see Sarges, 1989).

1 Chemistry

The development of aldose reductase inhibitors began in 1967, when tetramethyleneglutaric acid (TMG) was introduced as the first non-cytotoxic inhibitor of aldose reductase in experimental models (Kinoshita et al., 1968). Of more than a hundred potential aldose reductase inhibitors with in vitro

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