The chance observation by Janbon" in 1942 that p-aminosulfonamide caused hypoglycemia initiated an extensive search for oral hypoglycemic agents for diabetes mellitus. In the 20 years since Janbon's discovery, many agents have been studied. Some of them have been discarded after preliminary animal studies, whereas others have undergone clinical investigation in man before being abandoned. Ten oral hypoglycemic agents have been investigated in our clinic during the past 5 years; however, at the present time, only three of these drugs are currently on the market in this country. Two of these agents are sulfonylureas, and one is a diguanide.The two sulfonylureas that are generally available are tolbutamide and chlorpropamide, and the available diguanide is phenformin. The current status of these three drugs will be reviewed in this report, and a preliminary report of two new sulfonylurea agents will be added.
Pharmacology of some sulfonylurea drugsTolbutamide. According to Knauff,63 tolbutamide has a metabolic half-time of 4.7 hours. The relatively short half-life of this drug accounts for the fact that multiple doses are usually necessary for good control of diabetes. Dosage requirements for tolbutamide vary from 0.5 to 3 Gm. per day in two or three doses. Relatively few patients require more than 2 Gm. per day. Tolbutamide is metabolized in the body to carboxy tolbutamide and excreted in this form. Ninety-seven per cent of an administered dose may be recovered in the urine as carboxytolbutamide within 36 hours. 82 The mean half-life for the in vivo oxidation of tolbutamide to carboxy tolbutamide is 5.7 hours (range 4.4 to 6.85 hours). 83 The mean half-life for the excretion of carboxy tolbutamide is 0.49 hours (range 0.38 to 0.56 hours). Thus, on the average, this metabolite can be removed from the body about 12 times as rapidly as it is formed. H3 The peak hypoglycemic activity occurs within 4 to 6 hours after an oral dose of tolbutamide is administered. 71 o 0Chlorpropamide. The metabolic half-time of chlorpropamide is 35 hoursY: Actually, chlorpropamide appears to have two half-lives, presumably because of protein binding. The first half-life varies from 32 to 35 hours, and the second one is approximately 16 days in length. 9l Because of the long half-life, only one dose per day is necessary. The dosage required varies from 100 to 750 mg. per day. No hypoglycemic effect is noted during the first 2 hours after administration. A definite hypoglycemic effect is seen in 4 hours, but the peak activity does not develop until approximately 10 hours. The effect is still present 24 hours after administration. 3o Two metaholites of chlorpropamide have heen identified-
