Pharmacokinetics and biotransformation of chlorpropamide in man

Abstract

Chlorpropamide (CPA) pharmacokinetics were determined in 6 normal adult volunteers after a single oral 250 mg. dose. Drug absorption half-lifes varied from 0.1 to 1.5 hours with a calculated mean of 0.5 hour. Half-life for drug in plasma ranged from 25 to 42 hours with a calculated mean of 33 hours while the half-life estimated from urinary excretion data averaged 36 hours. In addition to drug, p-chlorobenzenesulfonylurea (CBSU),2-hydroxy-CPA (2-0H-CPA), and 3-hydroxy-CPA (3-0H-CPA) were recovered from urine of 4 diabetic subjects receiving 250 to 500 mg. of CPA daily. Approximately 2 per cent of daily dose was recovered from urine as p-chlorobenzenesulfonamide (CBSA), a degradation product of CBSU, and a similar amount was excreted as 3-0H-CPA. Drug, CBSU, and 2-0H-CPA excretion quantitated in 24 hour urine samples of these diabetic subjects by high-pressure liquid chromatography, averaged 18,21, and 55 per cent of dose, respectively. Two hours after CPA administration, unchanged drug accounted for 95 per cent of total drug and metabolite concentrations in plasma indicating that CBSU and 2-0H-CPA have significantly shorter elimination half-lifes than unchanged drug.

Clinical Pharmacology of Sulfonylureas

“…The absorption of chlorpropamide is almost complete (TAYLOR 1972) and in the absence of any first-pass effect complete absolute bioavailability was confirmed (HUUPPONEN and LAMMINTAUSTA 1981). Peak concentrations are reached between 3 and 6h or even later (TAYLOR 1972;TAYLOR et al 1977: NEUVONEN et a1.…”

“…In theory, rapid-acting agents with a pharmacokinetic profile independent of food intake should be preferred. The absorption rates vary among the different sulfonylureas, with the highest value being observed probably for glipizide (WAHLIN-BoLL et al 1982a), but similar also for gliquidone (KoPITAR and Koss 1975a,b), glibenclamide (HAUPT et al 1984;GROOP et al 1985;NEUGEBAUER et al 1985), tolbutamide (SARTOR et al 1980b), tolazamide (WELLING et al 1982) and lowest for gliclazide (CAMPBELL et al 1980;FORETTE et al 1982) and chlorpropamide (TAYLOR 1972;SARTOR et al 1980c). The absorption rate has been found to differ between formulations of the same compound, i.e., with tolbutamide (ÜLSON et al 1985), chlorpropamide (MONRO andWELLING 1974), glibenclamide (HAuPT et al 1984), tolazamide (WELLING et al 1982), gliquidone (KoPITAR andKoss 1975a,b) and glipizide (HAABER et a1.…”

“…Peak concentrations are reached between 3 and 6h or even later (TAYLOR 1972;TAYLOR et al 1977: NEUVONEN et a1. 1987) and rate of absorption but not its extent is decreased by food (SARTOR et a1.…”

“…Chlorpropamide undergoes extensive metabolism to 2-hydroxychlorpropamide (2-0H-CP), 3-hydroxychlorpropamide (3-0H-CP), p-chlorobenzenesulfonylurea (CBSU) and p-chlorobenzenesulfonamide (CBSA), a degradation product of CBSU (BROTHERTON et al 1969;TAYLOR 1972). Eighteen percent (10%-31%) is excreted as unchanged drug in urine, 55% (43%-69%) as 2-0H-CP, 21% (15%-25%) as CBSU and sm all amounts as 3-0H-CP (2%-3%) and CBSA (1.5%-4%), wh ich accounts for complete recovery.…”

Bioavailability of chlorpropamide.

“…It is a potent, long acting hypoglycaemic agent which acts by stimulating insulin secretion. Many workers (Beaser, 1959;Carlozzi, lezzoni & Silver, 1959;Handelsman, Levitt & Calabretta, 1959; Knauff, Fajans, Ramirez & Conn, 1959;West & Johnson, 1960) investigated aspects of the pharmacokinetics of chlorpropamide in the late 1950's and recently Taylor (1972) reported a more detailed study. Although the American Food and Drug Administration authority have listed chlorpropamide tablets as a formulation with a potential or known bioequivalence problem (Federal Register 1975), only two bioavailability studies appear to have been reported in the literature (Monro &Welling, 1974 andTaylor, Assinder, Chasseaud, Bradford &Burton, 1977 A plastic intravenous cannula was inserted into a forearm vein to facilitate blood sampling.…”