No abstract

High resolution 1H nuclear magnetic resonance (NMR) spectroscopic analysis of biofluids is a recently established tool for evaluating inherited and acquired errors in metabolic control. In the present study 1H NMR analysis of urine was used to monitor efficacy of BRL 49653, a potent and selective antihyperglycaemic agent, following oral administration for up to 36 weeks to the genetically diabetic C57BL/KsJ db/db mouse. The effects of BRL 49653 on carbohydrate and fatty acid metabolism were monitored by determination of changes in concentrations of low molecular weight urinary metabolites. A qualitative comparison of the NMR spectra of urine from untreated diabetic mice with those of lean littermates and literature examples revealed several abnormalities, the majority of which could be explained in terms of the non-insulin dependent diabetes syndrome exhibited by these animals. Quantitatively the most prominent was the extreme glycosuria of both young (8-12 weeks; 0.9 g glucose kg-1 h-1) and older (42 weeks; 2 g glucose kg-1 h-1) diabetic mice. This was accompanied by the excretion of a number of unassigned sugar derivatives and by ketone bodies. Administration of BRL 49653 (3 mumol kg-1) to db/db mice for 24 days reduced blood glucose concentrations to values comparable with non-diabetic lean littermates and reduced glycosuria by > 90%. BRL 49653 significantly reduced excretion of unassigned sugars, acetate, lactate, and the ketone bodies, acetoacetate, 3-D-hydroxybutyrate and acetone. The anti-diabetic efficacy of BRL 49653, assessed from the pattern of urinary metabolites, was maintained over a 36-week treatment period. These results demonstrate the value of 1H NMR to evaluate non-invasively the efficacy of novel therapeutic agents.

In the sera from 42 patients receiving quinidine, (3S)-3-hydroxyquinidine (3-OH), an active metabolite of quinidine, and quinidine were determined by high-pressure liquid chromatography with fluorescence detection. These results were added to those of 25 other patients reported previously. The 3-OH/quinidine ratio averaged 0.34 +/- 0.17 (SD) with a range of 0.10 to 0.90. Eleven patients (16%) had ratios above 0.50. After adjusting for protein binding differences between the 2 compounds, these 16% had 3-OH concentrations in serum water greater than that of quinidine. An additional 7 patients (10%) of the total) had levels of this metabolite in serum water slightly less than that of quinidine. A histogram showing the frequency distribution of 3-OH/quinidine in serum indicates extensive skewing with possibly a bimodal distribution with the antimode at 0.50. Thus, 3-OH may make a significant contribution to the effect of quinidine therapy in a fraction of treated patients. The clearance of quinidine decreased with age, indicating the need for, on the average, higher doses of quinidine in the young.