Metabolic Fate of Chlorpropamide in Man

“…13 The difference in hypoglycemic potency between dogs, on the one hand, and human beings and monkeys, on the other, may depend upon differences in metabolism. I t has been suggested4 that chlorination of the phenolic group prevented carboxylation of the compound in the para position, a reaction known to take place with tolbutamide in the human being."…”

Section: Discussionmentioning

confidence: 99%

The Pharmacology of Chlorpropamide

Schneider

Salgado

Jaeger

et al. 1959

Annals of the New York Academy of Sciences

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Ever since it was recognized that insulin could not be used orally in the treatment of diabetes mellitus, both synthetic compounds and natural products have been investigated for hypoglycemic activity pharmacologically and clinically. Severe side effects and/or insufficient activity made many of the previous attempts futile or impractical.The recent extensive studies of certain sulfonylureas as orally active hypoglycemic agents1* are the result of a concentrated research effort of the last sixteen years3 When the therapeutic value of the sulfonylureas was recognized, the search for the most effective compounds of the series was intensified. Chlorpropamide was selected as a result of an extensive screening program. Its high degree of hypoglycemic activity and prolonged duration of action as evidenced by animal experimentation warranted thorough pharmacological and clinical s t~d i e s .~ This paper summarizes the present status of pharmacological investigation with chlorpropamide, taking into account previous reports by Salgado et aL5 and Root.6 Emphasis is placed on new aspects; data corroborating earlier findings are referred to briefly. Materials and MethodsThe results reported were established in mice (Webster strain), rats (Wistar strain), cats, dogs, and rhesus monkeys. Routine pharmacological and biochemical methods were employed unless otherwise indicated.All blood sugar determinations were performed according to the method of Folin and Malmros.' The animals were fasted for 18 hours previous to the withdrawal of blood samples. Liver and muscle glycogen were determined by the method of Seifter.s Chlorpropamide blood levels were evaluated by a spectrophotometric method developed by Toolan and Wagner.g Where parenteral administ ration was employed, the sodium salt of chlorpropamide was used (solubility in water > 50 per cent; pH of 1 per cent solution = 8.5).Radioactive material consisted of Ss5-labeled chlorpropamide. ResultsHypoglycemic activity of chlorpropamide. As reported previously,6. 6 chlorpropamide was found to cause a prolonged hypoglycemic effect in both rats and dogs. Single oral doses of 25 mg./kg. or higher were required to obtain a definite effect. Calculated on a mg./kg. basis, this is at least twice the recommended average human dose (7 to 10 mg./kg./day). When compared to tolbutamide in these two species, chlorpropamide was somewhat slower in its onset, but more prolonged in its duration of action; the maximal hypoglycemic effect of both compounds was of approximately equal magnitude. 7Chlorpropamide was administered orally in most experiments.

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“…The drug is rapidly absorbed from the gastro-intestinal tract; in the serum it is bound to protein, and the half-life in the plasma has been estimated at 33 hr. It is excreted by the kidney and 70-80% of 35S-labelled chlorpropamide has been found unchanged in the urine after 72 hr (Johnson et al, 1959).…”

Section: Discussionmentioning

confidence: 99%