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Chlorpropamide Metabolite Levels in Serum

In the March-April issue of DIABETES CARE Campbell and Hansen addressed the paucity of information on the metabolism of chlorpropamide (CPA). Their inquiry to Pfizer laboratories, manufacturer of Diabinese, elicited the reply that as much as 80% of a dose of CPA could be accounted for in urinary metabolites. We and others have previously reported that protracted hypoglycemia in patients taking CPA occurs without the levels of intact CPA in the serum being extraordinarily high.' Also, serum CPA levels in diabetic patients taking the drug vary very little over the day, presumably because of long elimination times. After we developed techniques a few years ago for the measurement of oral antidiabetic sulfonylureas in serum by gas chromatography-mass spectrometry, we found that we could also measure the two major metabolites of CPA, p-chlorobenzene-sulfonylurea (CBSU) and 2-hydroxy-chlorpropamide (2-OH CPA). Table 1 shows that in seven nonuremic diabetic patients taking 500 mg Diabinese a day, there was considerable variation in the levels of CPA and of CBSU (8-53% of CPA) while the total /otg/ml of CPA plus metabolites was remarkably similar. The biological activity of CBSU is not known. Our preliminary data have given no hint as to whether variations in the metabolism of CPA have clinical significance. This question would seem worthwhile addressing, inasmuch as many type II diabetic patients are treated with CPA. This work was supported in part by grants from Pfizer Laboratories Inc. and the Upjohn Co. We thank Dr. R. S. Weinstein for obtaining most of the serum samples from his patients.