Indapamide metabolism

All thiazides and related compounds are well absorbed from the GIT and begin to produce diuresis within one hour after oral administration, but the duration is variable, which are due to variation in rates of renal tubular secretion and clearance, metabolism, and enterohepatic circulation. Approximately 50 percent of an oral dose is excreted in urine within 6 hours. Most of the agents undergo little hepatic metabolism and excreted as such. However indapamide is extensively metabolized. 

All thiazides can be administered orally, but there are differences in their metabolism. Chlorothiazide, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration. Chlorthalidone is slowly absorbed and has a longer duration of action. Although indapamide is excreted primarily by the biliary system, enough of the active form is cleared by the kidney to exert its diuretic effect in the DCT. 

The metabolic effects of indapamide appear to be as common as those of thiazides (SEDA-14, 185 SEDA-15, 216). The metabolic effects of hydrochlorothiazide 25 mg/day and indapamide 2.5 mg/day for 6 months have been compared in a randomized, double-blind study in 44 patients with mild to moderate hypertension (485). There was little difference between the effects of the drugs on a wide range of lipid parameters, glucose, and potassium. The purported metabolic differences with indapamide are unlikely to be of sufficient magnitude to warrant its preferential use in hyperlipidemia. 

Indapamide Indapamide [in DAP a mide] is a lipid soluble, nonthiazide diuretic that has a long duration of action. At low doses, it shows significant antihypertensive action with minimal diuretic effects. Indapamide is often used in advanced renal failure to stimulate additional diuresis on top of that achieved by loop diuretics. Indapamide is metabolized and excreted by the gastrointestinal tract and the kidneys it therefore is less likely to accumulate in patients with renal failure and may be useful in their treatment. 

Indapamide is extensively metabolized to at least 15 different metabolites. Only about 52 is excreted as unchanged drug in the urine (25,29). Several workers have suggested that hydroxylation of the indoline ring with conjugation may be a major route of metabolism (25). The glucuronide and sulphate conjugates of indapamide have been detected in the urine of patients (26). 

The fecal elimination is caused by the enterohepatic biliary recirculation of indapamide metabolites which in some subjects can be continued for 96 hours (25). However, elimination is essentially complete after 144 hours. The slow elimination in man may be due to enterohepatic recirculation and the long gastrointestinal tract transit time (24). Metabolic products in the feces are at least, a molecular weight of 500 indicating probable glucuronide and sulphate conjugates (26). 

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