Source: Health Products and Food Branch (CA) Revision Year: 2020 Publisher: sanofi-aventis Canada Inc., 2905 Place Louis-R.-Renaud, Laval, Quebec, H7V 0A3
ZAROXOLYN (metolazone) is a diuretic antihypertensive drug for the treatment of edema.
ZAROXOLYN is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of ZAROXOLYN result from interference with the renal tubular mechanism of electrolyte reabsorption. ZAROXOLYN acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal-tubular exchange site results in increased potassium excretion.
ZAROXOLYN does not inhibit carbonic anhydrase. A proximal action has been shown in humans by increased excretion of phosphate and magnesium ions, and by a markedly increased fractional excretion of sodium in patients with severely compromised glomerular filtration.
The antihypertensive mechanism of action of metolazone is not fully understood but is presumed to be related to its saluretic and diuretic properties.
The dominant pharmacologic actions of metolazone in animals are saluresis and diuresis. These effects have been demonstrated in rats and dogs and indicate an interference with the renal tubular mechanism of electrolyte reabsorption. The pattern of water and electrolyte excretion appears to be similar to that of some thiazides. Studies with desoxycorticosterone acetate saline-induced hypertension in rats have also demonstrated metolazone to be an effective antihypertensive agent; hypertension was reduced by metolazone, as well as inhibited by pretreatment with the drug.
Metolazone interferes with the renal tubular mechanism of electrolyte reabsorption and acts primarily to inhibit sodium reabsorption at the cortical diluting site of the distal segment and in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. Metolazone may also evoke a significant increase of potassium excretion in an amount sufficient to produce hypokalemia. With inhibition of sodium reabsorption, a higher concentration of this cation reaches the distal segment of the nephron and provides a more favorable milieu for the exchange process.
Metolazone produces a decrease in free water clearance in man and animals. Following intravenous administration of metolazone in doses up to 1 mg/kg, in hydrated dogs, free water clearance decreased, solute-free water reabsorption increased markedly, while the clearance of creatinine and PAH did not change significantly. Free water clearance is a function of sodium reabsorption in the cortical segment of the ascending Loop of Henle or early distal convoluted tubule. In most of the clinical studies, free water clearance diminished although urine flow increased, establishing a distal tubular site of action for metolazone.
In addition to this primary site of action in the cortical diluting segment, micropuncture and simultaneous clearance studies in dogs indicate a second site of action in the proximal tubule. In humans, a proximal site of action is inferred from measurements of excreted magnesium, phosphate and bicarbonate in the urine of hydrated and hydropenic subjects, from markedly increased fractional excretion of sodium and from increased excretion of phosphate and magnesium ions in patients with severely compromised glomerular filtration rate.
Metolazone possesses some carbonic anhydrase inhibitory action, and probably has a very slight action on bicarbonate transport by the kidney. The inhibition occurs in vitro only at high concentrations and, therefore, would appear to play little, if any, part in the diuretic action of the drug. The renal effects of the drug are virtually independent of alterations in acid-base balance. Dogs made acidotic or alkalotic by oral administration of ammonium chloride or sodium bicarbonate respectively, responded to intravenous administration of metolazone. Urinary sodium, potassium and chloride excretion are increased.
Metolazone does not significantly decrease the glomerular filtration rate in man, although in animals the effect is variable under different experimental conditions.
The drug exerted its natriuretic and diuretic effects on both normal and adrenalectomized rats. Its action, therefore, does not depend on aldosterone inhibition.
Metolazone is absorbed rapidly; however, rate and extent of absorption is dependent on the formulation. The table below shows that bioavailability of ZAROXOLYN is different from MYKROX (another product containing metolazone):
Pharmacokinetic Variables of Metolazone*:
| Formulation | 0-48hr AUC ng.hr/mL | 0-4 AUC ng.hr/mL | Cmax ng/mL | Tmax hr |
|---|---|---|---|---|
| Metolazone soln 2.5 mg | 230.59 (61.96) | 235.4 (61.50) | 37.50 (9.91) | 1.25 (0.44) |
| Mykrox 2.5 mg 199.40 (36.38) | 209.4 (41.00) | 18.75 (2.58) | 3.17 (1.03) | |
| Zaroxolyn 2.5 mg | 99.74 (28.97) | 127.0 (37.08) | 3.63 (0.87) | 7.67 (6.65) |
* Values presented are means (∀SD)
Studies in several species of animals indicate that metolazone is readily absorbed with an onset of diuretic effect within one (1) hour. Absorption is dose related up to levels of 50 mg/kg orally; the maximum effect is attained within 3-6 hours of oral administration.
Within 48 hours of an oral dose, 95% of the administered dose of metolazone is eliminated in the urine and feces of rats, dogs and monkeys. An average of 50% is eliminated unchanged.
Rat studies have shown metolazone to be distributed mainly in the soft tissue with little, if any, in the nerves, brain, bones or eyes. Metolazone passes readily through the placental barrier to the fetus and is found in the milk of lactating animals.
A single oral dose of 10 gm/kg was not lethal in rats, and a single intraperitoneal dose of 5 gm/kg was not lethal in mice. Acute effects in susceptible animals include electrolyte imbalance. Administration of single high doses (100 to 200 mg/kg) of metolazone intraperitoneally to rats caused a hyperglycemic effect, a decrease in liver glycogen, and an increase in plasma-free fatty acids. Adrenalectomy, nephrectomy, or pretreatment with α- and β-adrenergic blocking agents reduced this hyperglycemia significantly, suggesting than an adrenergic mechanism (possibly stress), as well as a renal mechanism, were involved.
Daily doses up to 50 mg/kg given orally for one year did not produce noticeable toxic effects in rats, dogs, or monkeys. Mild hypokalemia and slight elevation of blood urea nitrogen occurred in some of the dogs. In the majority of these cases, the abnormal value returned to near normal before the study ended and while the animals were still under treatment.
Long-term animal studies with metolazone have not shown any evidence of carcinogenicity. Mice and rats given the drug for 18 months to 2 years at doses of 2, 10 and 50 mg/kg by stomach tube, showed no evidence that metolazone caused an increased number of tumors; however, the small number of animals examined histologically, and poor survival in the mice, limit conclusions that can be reached from these studies.
A mutagenicity study using Salmonella typhimurium strains TA1535, TA97, TA98, TA100, and TA102 as indicator organisms and concentrations of 100 to 10,000 mcg/plate of metolazone showed no evidence of mutagenic potential.
Teratologic studies and studies of reproductive performance in mice, rats and rabbits (including a three-generation study with rats) treated with oral doses ranging from 0.2 to 50 mg/kg showed no evidence of teratologic effects. Reproductive studies in mice and rats have shown no evidence of altered reproductive capacity in mice; however, in a rat study in which males were treated orally with metolazone at doses of 2, 10 and 50 mg/kg for 127 days prior to mating with untreated females, an increased number of resorption sites were observed in dams mated with males from the 50 mg/kg group. In addition, the fetal weight was decreased and the pregnancy rate was reduced in dams mated with males from the 10 and 50 mg/kg group.
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