Pharmacokinetics and clinical pharmacology of indapamide.

Indapamide is a new antihypertensive diuretic agent indicated for the treatment of hypertension and edema. Indapamide shows an alteration in vascular reactivity to calcium and other agonists, suggesting the possibility of a direct vascular effect. The drug is recommended in doses of 2.5 to 5 mg once a day. It is rapidly and completely absorbed from the gastrointestinal tract, resulting in maximal blood levels in approximately 2.3 hours. Coadministration of indapamide with food or antacids does not reduce bioavailability. Linear proportionality of blood concentration with increasing doses is evident following both single and multiple doses. Other pharmacokinetic parameters are not dose related. Indapamide is widely distributed in the body with extensive binding to erythrocytes. Binding to plasma proteins is approximately 76%. Disappearance of indapamide from the blood is biphasic, with a terminal half-life of approximately 16 hours. Renal clearance represents less than 10% of the total systemic clearance of the parent drug, showing the dominant role of hepatic clearance. Studies of 14C-labeled indapamide in humans demonstrate that 70% of the radioactivity is excreted in urine and 23% in feces. Indapamide is extensively metabolized; less than 7% of the dose is excreted in urine as unchanged compound. Studies of patients with renal impairment showed little or no accumulation of indapamide in the blood in comparison to patients with normal renal function. Clinical studies demonstrate that indapamide has diuretic properties. Free water clearance studies indicate a site of action in the cortical diluting segment of the distal tubules. No adverse effect of indapamide on renal function is evident in normal volunteers, hypertensive patients, or geriatric hypertensive patients, as determined by glomerular filtration rate or effective renal plasma flow. Hemodynamic studies of indapamide in patients with mild to moderate hypertension show a significant (p less than 0.05) decrease in mean blood pressure (16%) and total peripheral resistance (15%). No other significant hemodynamic effects are evident. The data suggest that indapamide may produce antihypertensive activity through a dual mechanism of action--diuretic and direct vascular. Additionally, it appears to be safe even for patients with impaired renal function.