Metabolism of Chlorpropamide

Abstract

While recently reviewing the literature concerning the metabolic fate of chlorpropamide, we came across conflicting statements. In the following references it is stated that chlorpropamide is not metabolized to any significant extent and is highly protein bound: The Pharmacological Basis of Therapeutics, 6th edit., p. 1512; AM A Drug Evaluations, 4th edit., p. 753; Harrison's Principles of Internal Medicine, 8th edit., p. 574; Cecil's Textbook of Medicine, 15th edit., p. 1986; Physician's Desk Reference, 1980; and a Pfizer publication, Diabetes Mellitus Reference Book. The conclusion that can be drawn from this statement clinically is that chlorpropamide may be a good choice for diabetic patients who are suffering from liver disease. Furthermore, in diabetic patients with kidney disease, chlorpropamide would be contraindicated.The second edition of Applied Therapeutics for Clinical Pharmacists, p. 477, and the second edition of Drug Treatment by Graeme Avery, p. 505, state that chlorpropamide has variable hepatic metabolism (active metabolites) and a renal excretion of unchanged drug between 6-60%. Thus, the confusion: Is chlorpropamide metabolized or is it not? Even though Pfizer Laboratories states in the PDR, the package insert, and its Diabetes Mellitus Reference Book that chlorpropamide is not appreciably metabolized, we wrote to Pfizer to clear up the confusion. The response from Charles V. Bainbridge, Pharm. D., Assistant Director of Professional Services at Pfizer Laboratories, concerning the metabolic fate of chlorpropamide was as follows:Chlorpropamide has a biological half-life of about 36 hours. Within 96 hours, 80 to 90 percent of a single oral dose is excreted in the urine. 1 Classically, it was thought that chlorpropamide was not metabolized to any appreciable extent. 2 More recent studies using more sophisticated analytical techniques indicate that as much as 80 percent may be metabolized in diabetic patients. This may have been the result of early poor assay techniques. 3 The following was the analysis of the excretion in the urine:18% unchanged chlorpropamide (CPA) 21% p-chlorobenzenesulfonylurea (CBSU) 55% 2-hydroxyl CPA (2-OH CPA) 2% p-chlorobenzenesulfonamide (CBSA) 2% 3-hydroxyl CPA (3-OH-CPA) Two hours after chlorpropamide administration, unchanged drug accounted for 95 percent of the total drug and metabolite concentrations in plasma, demonstrating that CBSU and 2-OH CPA have shorter elimination halflives than unchanged drugs. 4 Unfortunately, the activity of these metabolites is unknown.Dr. Bainbridge went on to say that it would appear prudent to avoid the use of chlorpropamide in patients with tubular nephropathies since, as the half-life of chlorpropamide is increased, measurable serum metabolites of chlorpropamide also increase from 2% to 8%. He summarized the literature that states that chlorpropamide is not dialyzable and therefore dialysis as a method of controlling prolonged hypoglycemia in azotemic patients is not possible. 5 The fact that chlorpropamide is metabolized in some ...

Chlorpropamide 2‐hydroxylation is catalysed by CYP2C9 and CYP2C19 in vitro: chlorpropamide disposition is influenced by CYP2C9, but not by CYP2C19 genetic polymorphism

“…Additionally, pharmacokinetic characteristics varied even among subjects with the same CYP2C9 and CYP2C19 genotype. The pharmacokinetic characteristics of chlorpropamide may be partially responsible for this observation, since renal excretion is highly influenced by urinary pH and the percent of a chlorpropamide dose excreted into urine is reported to vary from 6 to 60%, depending on the urine pH [5, 39]. With urine acidification of subjects, indicating that renal excretion would not contribute to interindividual diversity of chlorpropamide kinetics, the differences in plasma concentration and pharmacokinetic parameters between groups of CYP2C9 genotype seem to be more evident.…”

“…Rifampin, a known inducer of CYP enzymes, has been reported to decrease significantly the plasma concentration of coadministered chlorpropamide, and thus increase the effective chlorpropamide dosage, after concomitant administration [10]. Furthermore, plasma chlorpropamide concentrations increase in the presence of coadministered drugs known to inhibit CYP enzymes [5]. These observations suggest that the metabolic fate of chlorpropamide contributes markedly to its interindividual pharmacokinetic variation in human, and genetic polymorphisms of the CYP isoform(s) participating in the chlorpropamide metabolism may also be responsible for the wide individual variability in chlorpropamide disposition.…”

“…Chlorpropamide is extensively metabolized in human liver: as much as 80% of a single chlorpropamide dose and several of its metabolites, including 2‐hydroxychlorpropamide (2‐OH‐chlorpropamide), 3‐hydroxychlorpropamide, p ‐chlorobenzene‐sulphonylurea, and p ‐chlorobenzene‐sulphonamide, were identified in human urine after oral dosing [3, 4]. In humans, 2‐hydroxylation is the principal metabolic fate of chlorpropamide; 2‐OH‐chlorpropamide recovered in urine accounts for approximately 43–69% of the daily dose [5].…”