A study of the metabolic fate of chlorpropamide in man

Brotherton, P. M.; Grieveson, Phillida; McMartin, Colin

doi:10.1002/cpt1969104505

Cited by 43 publications

(11 citation statements)

References 4 publications

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“…Chlorpropamide was extensively metabolized in human liver up to 80% of a single dose and several of its metabolites, including 2-hydroxychlorpropamide, 3-hydroxychlorpropamide, pchlorobenzene sulphonylurea, and p-chlorobenzene sulphonamide, were identified in human urine after oral dosing (Fig. (118)) [982,983]. 2-OH-chlorpropamide was formed by both CYP2C9 and 2C19 [984].…”

Section: Chlorpropamidementioning

confidence: 98%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Chlorpropamidementioning

confidence: 98%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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“…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.…”

Section: C) Metabolismmentioning

confidence: 99%

Clinical Pharmacology of Sulfonylureas

Groop¹,

Neugebauer²

1996

Oral Antidiabetics

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“…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.…”

mentioning

confidence: 97%

“…This may have been the result of early poor assay techniques. 3 The following was the analysis of the excretion in the urine:…”

mentioning

confidence: 99%

Metabolism of Chlorpropamide

1981

Diabetes Care

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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 ...

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A study of the metabolic fate of chlorpropamide in man

Cited by 43 publications

References 4 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Clinical Pharmacology of Sulfonylureas

Metabolism of Chlorpropamide

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