Acetohydroxamic Acid (Monograph)

Drug class: Ammonia Detoxicants
- Urease Inhibitors
VA class: AD400
Chemical name: N-Hydroxyacetamide
Molecular formula: C₂H₅NO₂
CAS number: 546-88-3

Medically reviewed by Drugs.com on Nov 21, 2024. Written by ASHP.

Introduction

Acetohydroxamic acid, a urease inhibitor, is an ammonia detoxicant.

Uses for Acetohydroxamic Acid

Urinary Tract Infections

Acetohydroxamic acid is considered an orphan drug and is used as an adjunct to appropriate anti-infective and surgical (in patients with renal calculi) therapy in patients with chronic urinary tract infections caused by urease-producing bacteria; the safety and efficacy of the drug as an adjunct in the management of these infections have been determined in a limited number of patients. Acetohydroxamic acid does not directly acidify the urine and the manufacturer states that it does not have a direct anti-infective effect. (See Pharmacology: Antibacterial Effect.) Although acetohydroxamic acid inhibits the production of ammonia and prevents the resultant increase in urinary pH, therapy with the drug should not replace appropriate anti-infective therapy and/or surgical removal of a urinary calculus when the stone is contributing to chronic urinary tract infections and surgery is not contraindicated. The drug should not be used in patients whose urine is infected with bacteria that do not produce urease. Long-term therapy with acetohydroxamic acid may be necessary to inhibit urease in some patients when urinary tract infection with urease-producing bacteria is prolonged; however, the manufacturer states that the safety and efficacy of acetohydroxamic acid therapy for periods longer than 7 years have not been determined.

Acetohydroxamic acid appears to contribute to the efficacy of anti-infective agents following surgical removal of urinary struvite calculi in patients with urinary tract infections caused by urease-producing bacteria (usually Proteus) that are unresponsive to 3–6 months of therapy with anti-infectives alone; additional studies to confirm this finding are needed. In addition to apparently contributing to the efficacy of certain anti-infectives, acetohydroxamic acid appears to have a beneficial effect on infection-induced urinary calculi in patients with urinary tract infections caused by urease-producing bacteria. The drug has reportedly indirectly inhibited the formation of new struvite and/or carbonate-apatite crystals, retarded the growth of new or existing calculi, and/or partially dissolved existing calculi in these patients when surgical removal was not feasible and in other patients who had recurring calculi despite appropriate anti-infective and surgical therapy. While not clearly established, chronic administration of acetohydroxamic acid may decrease the incidence of recurrent stones in patients who have undergone surgical removal of infection-induced urinary calculi and who have chronic urinary tract infections. Some clinicians have suggested that administration of the drug during the period immediately following surgical removal of infection-induced calculi may be beneficial, since small fragments of calculi, representing potential nidi for calculus and infection recurrence, may remain following surgery. Some clinicians believe that acetohydroxamic acid is most likely to be effective in preventing or minimizing stone growth or recurrence in patients with relatively good renal function and minimal obstruction and stasis within the renal collecting system. Additional study is needed to fully determine the effects of acetohydroxamic acid on infection-induced urinary calculi in patients with chronic urinary tract infections caused by urease-producing bacteria.

Hepatic Coma

Acetohydroxamic acid has been used in a few patients for the management of hepatic coma^{† [off-label]} when hydrolysis of urea via bacterial urease in the GI tract was thought to be a major cause of increased blood ammonia concentration. Following oral administration of an acetohydroxamic acid solution in patients with hepatic failure that had progressed to coma despite dietary protein restriction and neomycin therapy, the mean blood ammonia concentration was decreased during the 6-hour period following administration of the drug. There appeared to be no consistent clinical response; several patients died within 48 hours despite therapy, but one patient responded with a temporary lessening of coma, return of response to painful stimuli, and improved EEG pattern, and another patient had a rapid return to consciousness and gradual but temporary improvement. Further studies are needed to determine the safety and efficacy of acetohydroxamic acid in the management of hepatic coma. Other forms of therapy such as dietary protein restriction, neomycin, and/or lactulose are preferred.

Acetohydroxamic Acid Dosage and Administration

Administration

Acetohydroxamic acid is administered orally. Although the manufacturer states that acetohydroxamic acid should always be administered at a time when the stomach is empty, the effect of food on GI absorption of the drug has not been determined. Absorption of the drug may potentially be reduced by dietary metals (e.g., iron). (See Drug Interactions: Iron.)

Dosage

To obtain optimum results, patients should be given a copy of the patient information provided by the manufacturer. Patients should be advised of the importance of complying with the prescribed dosage regimen for acetohydroxamic acid, since failure to comply may result in decreased efficacy of the drug and recurrence of stone formation.

Adult Dosage

The usual initial adult dosage of acetohydroxamic acid is 250 mg 3 or 4 times daily (about 12 mg/kg daily), given at 6- to 8-hour intervals. A total daily dose of 10–15 mg/kg (not to exceed 1.5 g), given in divided doses, is recommended for adults.

Pediatric Dosage

The usual dose and frequency of administration of acetohydroxamic acid in children have not been established; however, the manufacturer states that an initial dosage of 10 mg/kg daily administered in 2 or 3 divided doses has been tolerated satisfactorily for periods up to 1 year in children 8–10 years of age. Close monitoring of the child’s clinical condition and hematologic status is recommended. Dosage should be adjusted according to individual tolerance and response, using the lowest possible effective dosage.

Dosage in Renal Impairment

The optimum dose and frequency of administration of acetohydroxamic acid in patients with moderate degrees of renal impairment have not been determined. In patients with serum creatinine concentrations of 1.8–2.5 mg/dL, the manufacturer currently recommends that the total daily dose of acetohydroxamic acid not exceed 1 g, given in 2 divided doses at 12-hour intervals; however, pending further accumulation of data, some clinicians recommend that the drug be used with extreme caution in patients with a serum creatinine concentration of 1.3–2.5 mg/dL and that total daily dose also not exceed 1 g in patients with a serum creatinine concentration of 1.3–1.8 mg/dL. These clinicians also recommend that serum creatinine concentration be determined periodically and monitored closely during therapy with the drug in patients with renal impairment or changing renal function. Additional dosage reduction may be necessary to prevent the accumulation of toxic concentrations of the drug. The drug should not be administered to patients with serum creatinine concentration greater than 2.5 mg/dL or creatinine clearance less than 20 mL/minute. (See Cautions: Precautions and Contraindications.)

Cautions for Acetohydroxamic Acid

The manufacturer states that experience with acetohydroxamic acid is limited but that the drug has been administered to most patients for periods of more than 1 year. Adverse effects, including only abnormal laboratory test results in some patients, have occurred in up to 30% of patients receiving the drug. Adverse effects occur most frequently in patients with preexisting thrombophlebitis or phlebothrombosis and/or advanced degrees of renal impairment and during the first year of therapy with acetohydroxamic acid; chronic administration of the drug does not appear to be associated with an increased risk or severity of adverse effects.

Nervous System Effects

Headache, appearing during the first 48 hours of treatment, reportedly occurs in approximately 30% of patients receiving acetohydroxamic acid; however, several clinicians reported that mild, transient headache occurred in 70–75% of patients during initiation of therapy. Headache is generally mild, responsive to oral salicylate analgesics, and usually disappears spontaneously. Headache has not been associated with vertigo, tinnitus, or visual or auditory disturbances. Malaise occurs in about 20–25% of patients receiving the drug.

Mental depression, anxiety, nervousness, and tremulousness have occurred in approximately 20% of patients receiving acetohydroxamic acid and are usually mild and transient; however, these effects have been sufficiently severe to necessitate reduction in dosage, or interruption or discontinuance of therapy in some patients.

GI Effects

Adverse GI effects including nausea, vomiting, anorexia, diarrhea, and constipation reportedly occur in approximately 20–25% of patients receiving acetohydroxamic acid; although these effects have been reported in up to 50% of patients, a causal relationship to the drug was considered questionable in many of these patients. Adverse GI effects are usually mild, transient, and generally do not require discontinuance of therapy.

Hematologic Effects

Hemolytic anemia that was negative for direct antiglobulin (Coombs’) test has occurred in patients receiving acetohydroxamic acid. Adverse hematologic effects occur most frequently in patients with advanced renal failure. A mild (5–6%) reticulocytosis without other signs of anemia occurs in more than 15% of patients receiving the drug. Approximately 15% of patients receiving acetohydroxamic acid have only abnormal laboratory test results characteristic of anemia. Severe anemia has been reported in 3% of patients. When severe, the hemolytic anemia is often accompanied by GI disturbances (e.g., nausea, vomiting, anorexia), generalized malaise, lethargy, and fatigue; however, abnormal laboratory test results and other adverse effects generally improve upon discontinuance of the drug. Administration of the drug at reduced dosage has been continued in several patients without recurrence of signs or symptoms of hemolytic anemia.

Hemoglobin concentration has decreased by more than 2 g/dL in several patients receiving acetohydroxamic acid; this may result from chelation of dietary iron by the drug. (See Drug Interactions: Iron.) Hemolysis, associated with a decrease in circulating erythrocytes, hemoglobin concentration, and hematocrit, has been reported in patients receiving the drug. Although the manufacturer states that thrombocytopenia has not been reported, nonpathologic transient thrombocytopenia has occurred in several patients. Bone marrow depression has occurred in animals receiving large doses of the drug but has not been reported to date in humans. However, the possibility that acetohydroxamic acid could cause bone marrow depression should be considered, since the drug has been shown to inhibit DNA synthesis.

Dermatologic Effects

Alopecia has reportedly occurred in about 10% of patients receiving acetohydroxamic acid. Scalp tenderness has also occurred. A nonpruritic, macular rash has occurred on the upper extremities and face of several patients receiving chronic therapy with the drug; although the rash occurs most frequently in patients who ingest alcohol concomitantly, it has occurred in the absence of alcohol consumption in a few patients. (See Drug Interactions: Alcohol.) Excessive sweating has also been reported in patients receiving the drug.

Cardiovascular Effects

Superficial phlebitis involving the lower extremities has occurred in several patients receiving acetohydroxamic acid during preliminary clinical studies; several of these patients had a history of phlebitis. One patient who had experienced a traumatic injury to the groin developed deep-vein thrombosis of the lower extremities while receiving the drug and 2 other patients reportedly developed deep-vein thrombosis of the lower extremities while receiving the drug. However, it is unclear whether phlebitis is causally related or exacerbated by acetohydroxamic acid therapy. There was radiographic evidence of small pulmonary emboli in a few patients who developed phlebitis in the lower extremities during preliminary clinical studies with the drug; however, respiratory symptoms were not present in these patients. Phlebitis and/or associated emboli have resolved following discontinuance of the drug and initiation of appropriate medical treatment. An unconfirmed diagnosis of pulmonary embolism was reported in one patient who presented with cardiopulmonary symptoms and signs of lower extremity phlebitis following 6 weeks of acetohydroxamic acid treatment. In several patients who developed phlebitis, therapy with acetohydroxamic acid was reinstituted without evidence of recurrence of these adverse effects; however, some clinicians suggest that it may be advisable to avoid use of the drug in patients with a history of deep-vein thrombosis or in those predisposed to phlebothrombosis.

Palpitation has also been reported in patients receiving acetohydroxamic acid.

Precautions and Contraindications

Acetohydroxamic acid should only be used in carefully selected patients. Therapy with the drug should not replace appropriate anti-infective therapy and/or surgical removal of a urinary calculus when indicated. The drug should not be used in patients whose physical condition or disease can be corrected by definitive surgery and/or appropriate anti-infective therapy or in those whose urine is infected with bacteria that do not produce urease.

Platelet and leukocyte counts should be monitored during acetohydroxamic acid therapy, since bone marrow depression, characterized by leukopenia, anemia, and thrombocytopenia, has occurred in animals receiving large doses of the drug. A complete blood count, including reticulocyte count, should be performed 2 weeks after initiation of therapy with the drug and then repeated at 3-month intervals for the duration of drug therapy, since hemolytic anemia and reticulocytosis may occur. (See Cautions: Hematologic Effects.) If the reticulocyte count exceeds 6%, a reduction in dosage should be considered.

Although abnormal liver function test results have not been reported to date in patients receiving acetohydroxamic acid, a chlorobenzene derivative of the drug has caused substantial liver dysfunction; therefore, liver function should be monitored closely during acetohydroxamic acid therapy.

Patients should be advised to report any unusual adverse effects that occur during acetohydroxamic acid therapy to their physician. Although mild drug-induced adverse effects usually do not require discontinuance of therapy, severe effects may require a temporary dosage adjustment and/or discontinuance of the drug. Patients should also be advised that oral preparations containing iron should not be taken concomitantly with acetohydroxamic acid. (See Drug Interactions: Iron.) Patients should be encouraged to abstain from consuming alcoholic beverages during therapy with the drug. (See Drug Interactions: Alcohol.) Patients should be advised of the importance of complying with the prescribed dosage regimen, since failure to comply may result in decreased efficacy of the drug and recurrence of stone formation; if anti-infectives are used concomitantly, the patient should be instructed to carefully follow the prescribed regimen so that optimum efficacy may be achieved.

Since a substantial portion of acetohydroxamic acid is excreted unchanged in urine, patients with substantial renal impairment should be closely monitored, and a reduction in dosage may be necessary to prevent accumulation. (See Dosage and Administration: Dosage in Renal Impairment.) Some clinicians recommend that, pending further accumulation of data, the drug be used with extreme caution in patients with a serum creatinine concentration of 1.3–2.5 mg/dL. Acetohydroxamic acid is contraindicated in patients with a serum creatinine concentration greater than 2.5 mg/dL and/or creatinine clearance less than 20 mL/minute, since the risks of toxic concentrations of the drug seem to outweigh any possible benefits in these patients. Acetohydroxamic acid also is contraindicated in women who are or may become pregnant, and therapy with the drug should not be initiated in women of childbearing potential until the possibility of pregnancy has been excluded and an effective method of contraception has been started. (See Cautions: Pregnancy and Lactation.)

Pediatric Precautions

Children with chronic, resistant urinary tract infections caused by urease-producing bacteria may benefit from acetohydroxamic acid therapy; however, the dose and frequency of administration in children have not been established. (See Pediatric Dosage, in Dosage and Administration: Dosage.) If the drug is used in a child, the patient should be closely monitored.

Mutagenicity and Carcinogenicity

Well-controlled, long-term animal studies to determine the carcinogenic potential of acetohydroxamic acid have not been performed to date; however, in long-term studies in rats, large oral dosages (e.g., 4 g/kg daily) of acetamide, a metabolite of acetohydroxamic acid, have been shown to cause hepatocellular carcinoma. Acetohydroxamic acid is cytotoxic and has shown mutagenic activity in the Ames microbial mutagen test.

Pregnancy and Lactation

Pregnancy

Acetohydroxamic acid may cause fetal harm when administered to pregnant women. The drug has been shown to be teratogenic in rats, causing retarded and/or clubbed rear leg, exencephaly, encephalocele, cleft palate, and ectrodactyly and polydactyly when given intraperitoneally at doses of 750–1500 mg/kg. The teratogenic effects and dose relationships in these rats were similar for acetohydroxamic acid and hydroxyurea; the fetuses were more sensitive to the lethal effects of the drugs than were the mothers. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, acetohydroxamic acid is contraindicated in such women. Women of childbearing age should be instructed to use an effective form of contraception during acetohydroxamic acid therapy and informed of the potential hazard to the fetus should they become pregnant during therapy with the drug. If the drug is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug, the potential hazard to the fetus should be considered.

Lactation

It is not known if acetohydroxamic acid is distributed into milk. Because of the potential for serious adverse reactions to acetohydroxamic acid in nursing infants, a decision should be made whether to discontinue nursing or to not use the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Alcohol

A nonpruritic, macular rash has occurred on the upper extremities and face of several patients receiving chronic therapy with acetohydroxamic acid; although the rash occurred most frequently in patients who ingested alcohol concomitantly, it occurred in the absence of alcohol consumption in a few patients. The rash characteristically appears 30–45 minutes after ingestion of alcohol and disappears spontaneously after about 30–60 minutes. The rash may be associated with a general sensation of warmth and may be sufficiently severe in some patients to necessitate discontinuance of the drug; however, in most patients, acetohydroxamic acid therapy may be continued with special attention given to avoiding or consuming smaller amounts of alcohol.

Iron

Because of the drug’s chelating properties, acetohydroxamic acid may interfere with the metabolism of some metals (e.g., iron). The absorption of iron and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly; chelation of iron may interfere with hematopoiesis. (See Cautions: Hematologic Effects.) When iron therapy is indicated in a patient receiving acetohydroxamic acid, the manufacturer states that the iron should probably be administered parenterally rather than orally.

Methenamine

In vitro studies indicate that acetohydroxamic acid and methenamine have a synergistic effect in inhibiting increases in pH caused by urease-producing Proteus spp. and that acetohydroxamic acid potentiates the antibacterial effect of methenamine against these bacteria; these results suggest that concomitant administration of the drugs may be useful in the management of chronic urinary tract infections caused by urease-producing Proteus spp. susceptible to methenamine.

Other Drugs

The manufacturer states that acetohydroxamic acid has been administered concomitantly with insulin, oral and parenteral anti-infectives, and progestational agents. Although no clinically important drug interactions were reported in patients receiving these drugs, acetohydroxamic acid should be administered with caution in patients receiving other therapeutic agents.

The manufacturer states that patients should be advised to not take prescription or over-the-counter medications concomitantly with acetohydroxamic acid unless they have first consulted with their physician.

Laboratory Test Interferences

Although acetohydroxamic acid is a urease inhibitor and chelates iron, the drug reportedly does not interfere with determination of urea nitrogen by the urease-Berthelot, urease-glutamate dehydrogenase, or diacetyl monoxime method.

Acute Toxicity

The manufacturer states that there has been no experience to date with intentional, acute overdose of acetohydroxamic acid.

Pathogenesis

The LD₅₀ in mice following intraperitoneal or oral administration of acetohydroxamic acid has been reported to be 2.5 and 5 g/kg, respectively; all deaths occurred within 24 hours after administration. Evidence of toxicity did not occur when the drug was administered subcutaneously in mice at a dosage of 500 mg/kg daily for 60–100 days; however, evidence of cumulative toxicity, with death occurring at a mean of 21 days, occurred when the drug was administered subcutaneously at a dosage of 1 g/kg daily. The manufacturer states that the LD₅₀ of acetohydroxamic acid in rats is 4.8 g/kg. No evidence of toxicity was present in dogs following repeated oral administration of 60 mg/kg.

Manifestations

Overdosage of acetohydroxamic acid is likely to produce symptoms that are mainly extensions of common adverse reactions including anorexia, malaise, lethargy, diminished sense of well-being, tremulousness, anxiety, nausea, and vomiting. Laboratory evidence of thrombocytopenia, leukopenia, reticulocytosis, and severe hemolytic anemia is also likely.

Treatment

In acute acetohydroxamic acid overdose, supportive and symptomatic treatment should be initiated. Hematologic function should be monitored closely (see Cautions: Hematologic Effects), and blood transfusions administered when necessary.

The manufacturer states that although elimination of acetohydroxamic acid is probably enhanced by dialysis, clinical studies to determine the effect of dialysis have not been conducted to date.

Pharmacology

Urease Inhibition

Acetohydroxamic acid is a urease inhibitor. The drug causes an irreversible, noncompetitive inhibition of the enzyme urease, and thus inhibits the hydrolysis of urea and subsequent production of ammonia in urine infected with urease-producing bacteria. The drug may also inhibit urease activity of the GI mucosa and bacterial flora. In vitro, acetohydroxamic acid is a more potent urease inhibitor than is hydroxyurea or hydroxylamine. Unlike hydroxyurea, acetohydroxamic acid itself does not undergo hydrolysis by urease. Acetohydroxamic acid appears to inhibit urease by forming a complex with, rather than by oxidizing, the enzyme. The drug is specific in its action for urease and reportedly lacks inhibitory effects on most other enzymes. Acetohydroxamic acid inhibits urease at pH 5–9 and is most effective at pH 7.

Effect on Urinary pH

Acetohydroxamic acid does not directly affect urinary pH and should not be considered an acidifying agent. By inhibiting formation of ammonia, the drug prevents the increased pH that occurs in urine infected with urease-producing bacteria. Following administration of a single 1-g dose of acetohydroxamic acid in several patients with urine infected with urease-producing bacteria, mean urinary pH decreased from greater than 6.6 prior to administration of the drug to 5.7 during the first 24-hour period after administration; pH increased to a mean of 6.1 and 6.3 during the second and third 24-hour periods after administration of the drug, respectively. In another study in patients with chronic urinary tract infections, urinary pH decreased from a mean of 7.1 prior to therapy with the drug to 6.64 during therapy (250 mg 3 times daily for 7 days); pH returned to pretreatment levels following discontinuance of the drug. Following administration of 500 mg of acetohydroxamic acid twice daily for 2 weeks in several other patients with these infections, urinary ammonia excretion and pH were decreased to less than pretreatment values; however, values after 2 weeks of therapy were not decreased to within normal limits (i.e., 24-hour ammonia excretion less than 800 mg and pH less than 6.5) in all patients.

Antibacterial Effect

Acetohydroxamic acid-induced reductions in urinary ammonia concentration and pH reportedly enhance the effectiveness of certain anti-infective agents against urinary tract infections caused by urease-producing bacteria and thus may increase the likelihood of microbiologic cure. One in vitro study indicates that the antibacterial activity of acetohydroxamic acid and ampicillin, carbenicillin, cephalothin (no longer commercially available in the US), chloramphenicol, clindamycin, gentamicin, kanamycin, nalidixic acid, streptomycin, or tetracycline may occasionally be synergistic against some organisms including Escherichia coli, Klebsiella spp., Morganella morganii (formerlyProteus morganii), Providencia rettgeri (formerly Proteus rettgeri), and Pseudomonas aeruginosa; however, antibacterial antagonism may also occur. Although in vitro synergism was observed only occasionally overall, it occurred most frequently with acetohydroxamic acid and carbenicillin, chloramphenicol, clindamycin, or gentamicin. Although the manufacturer states that acetohydroxamic acid does not exhibit a direct antibacterial effect, the drug has been reported to have a concentration-dependent bacteriostatic effect against some strains of urease-producing and non-urease-producing gram-negative bacteria in vitro, but relatively high concentrations of the drug are required.

Effects on Infection-induced Urinary Calculi

Hydrolysis of urea in urine infected with urease-producing bacteria not only increases urinary ammonia concentration and pH but also increases urinary concentration of bicarbonate and carbonate; these effects contribute to the formation of crystals or calculi (stones). By inhibiting ammonia, bicarbonate, and carbonate production and thereby decreasing urinary pH, acetohydroxamic acid appears to indirectly inhibit formation of new crystals and calculi (struvite, carbonate-apatite) and retard the growth of or partially dissolve existing crystals or calculi that form in alkaline urine supersaturated with magnesium ammonium phosphate (struvite) and/or calcium phosphate. The drug’s effects on infection-induced renal calculi and the mechanisms involved have not been fully characterized. Following short-term acetohydroxamic acid therapy in patients who had chronic urinary tract infection with urease-producing bacteria and urinary calculi, urinary ammonia excretion and pH were decreased, but relative saturation of urinary magnesium ammonium phosphate was reportedly only minimally reduced and urinary excretion of magnesium and phosphate was increased. Characterization of the effects following long-term therapy is needed.

Other Effects

Acetohydroxamic acid has been shown to inhibit DNA synthesis in HeLa cells in vitro, apparently by inhibiting incorporation of thymidine into DNA. The drug has cytotoxic activity; in rats, acetohydroxamic acid has about one-tenth the cytotoxic activity of hydroxyurea on a molar basis. Acetohydroxamic acid also chelates metals (e.g., iron); the drug chelates iron by binding ferric ions.

Acetohydroxamic Acid Pharmacokinetics

Absorption

Acetohydroxamic acid is rapidly absorbed following oral administration; absorption occurs mainly in the upper GI tract and to a much lesser extent from the colon. In animals, the absolute bioavailability following oral administration has been reported to be about 50 and 60% following a single 50- and 100-mg/kg dose, respectively. Following oral administration of a single 250-mg dose in humans, peak serum acetohydroxamic acid concentrations of about 8–12 mcg/mL occur within 15–60 minutes.

Distribution

Acetohydroxamic acid is distributed throughout total body water. In mice, highest concentrations of the drug occur in the liver and kidney, while the lowest concentrations occur in the brain. The apparent volume of distribution of acetohydroxamic acid has been reported to range from 24.5–53.3 L in a few healthy adults following oral administration of a 250-mg dose. In rats, the volume of distribution of the drug reportedly increases with increasing dose. The drug apparently does not bind to tissues.

It is not known if acetohydroxamic acid is distributed into milk in humans.

Elimination

The elimination of acetohydroxamic acid has not been fully characterized in humans. In rodents, the elimination of acetohydroxamic acid is dose dependent; as dosage is increased, the plasma half-life and fraction of a dose excreted unchanged in urine increase and total body clearance decreases. In rodents, about 55% of an intraperitoneal dose is excreted in urine as unchanged drug, 15% as acetamide, and 10% as acetate within 24 hours; approximately 7% of the dose is excreted by the lungs as CO₂ and less than 1% is excreted in feces within 24 hours.

In humans, the elimination of acetohydroxamic acid also appears to be dose dependent. The plasma half-life of acetohydroxamic acid appears to increase with increasing dose and reportedly ranges from about 3.5–10 hours in patients with normal renal function. In a few adults with normal renal function (creatinine clearance greater than 90 mL/minute), the plasma half-life has been reported to be about 3.5–5, 8, or 7.6–10 hours following administration of a single 250-, 500-, or 1000-mg dose, respectively. The half-life of the drug is prolonged in patients with impaired renal function. In an adult with a creatinine clearance of 28 mL/minute, the serum half-life was reportedly 17.5 hours following administration of a single 500-mg dose. The plasma half-life of acetohydroxamic acid may also be prolonged in patients with hepatic dysfunction.

Acetohydroxamic acid is metabolized to acetamide. Formation of acetamide may be a capacity-limited (saturable) process; with increasing doses, the relative amount of drug excreted in urine unchanged increases while the relative amount excreted as acetamide decreases. Acetamide does not inhibit urease. Additional study on the metabolic clearance of the drug in humans is necessary.

Acetohydroxamic acid is excreted principally in urine. Approximately 35–65% of an orally administered dose is excreted unchanged in urine within 24–48 hours in patients with normal renal function; less than 10% is excreted in urine as acetamide. Following oral administration of the drug in a few adults with normal renal function, about 37–53, 43–55, or 53–65% of a single 250-, 500-, or 1000-mg dose of acetohydroxamic acid was excreted unchanged in urine within 48 hours. The fraction of a dose excreted in urine is decreased in patients with impaired renal function. In patients with creatinine clearances of 64–67 mL/minute, 16–20% or 13–24% of a single weekly 500- or 1000-mg dose, respectively, was excreted within the first 8 hours; in patients with creatinine clearances of 32–35 mL/minute, 2–15% or 9–20% of a single weekly 500- or 1000-mg dose, respectively, was excreted within the first 8 hours. Following multiple-dose administration of 500 mg twice daily in one study, 37–75% of the administered dose was excreted in urine within 24 hours in patients with a creatinine clearance of 70 mL/minute or greater; in 2 patients with a creatinine clearance of 45 or 25 mL/minute, 21 or 27% of the dose, respectively, was excreted in urine within 24 hours.

Unchanged acetohydroxamic acid in urine is the pharmacologically active form of the drug; however, the optimum therapeutic urinary concentration has not been established. Therapeutic effect has been observed with urinary concentrations of 8–70 mcg/mL; concentrations in the upper end of this range (e.g., 30 mcg/mL or greater) may be expected to provide greater inhibition of urease than lower concentrations. In one study, oral administration of 500 mg of acetohydroxamic acid twice daily resulted in urinary concentrations ranging from 80 mcg/mL in a patient with a creatinine clearance of 45 mL/minute to 320 mcg/mL in a patient with normal renal function; in a study in patients whose renal function was not determined, oral administration of 250 mg every 8 hours resulted in urinary concentrations of 100–500 mcg/mL.

It is not known if acetohydroxamic acid is dialyzable.

Chemistry and Stability

Chemistry

Acetohydroxamic acid is a urease inhibitor that is structurally similar to urea and hydroxyurea. Acetohydroxamic acid is a synthetic hydroxamic acid derived from hydroxylamine hydrochloride and ethyl acetate. Acetohydroxamic acid differs structurally from hydroxyurea by the presence of a methyl rather than an amino group; the N-hydroxyformamide (formohydroxamic acid) moiety appears to be responsible for urease inhibition.

Acetohydroxamic acid occurs as white crystals and has solubilities of 850 and 400 mg/mL in water and in alcohol, respectively. The drug has a pK_a of 9.32–9.4. Aqueous solutions of the drug have a pH of about 9.4.

Stability

Acetohydroxamic acid tablets should be stored in tight containers.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.