Isoniazid excretion

In an experimental study of the possible effects of laxatives on isoniazid absorption, healthy subjects were given 10 to 20 g of oral sodium sulfate or 20 g of castor oil (doses sufficient to provoke diarrhoea). Absorption, measured by the amount of isoniazid excreted in the urine, was decreased by 50% with castor oil and by 41% with sodium sulfate at 4 hours. However, serum levels of isoniazid were relatively unchanged. The overall picture was that while these laxatives can alter the pattern of absorption, they do not seriously impair the total amount of drug absorbed. ... 

Excretion - Approximately 50% to 70% of a dose of isoniazid is excreted as unchanged drug and metabolites by the kidneys in 24 hours. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

Isoniazid is acetylated to acetyl isoniazid by A-acetyl-transferase, an enzyme in fiver, bowel, and kidney. Individuals who are genetically rapid acetylators will have a higher ratio of acetyl isoniazid to isoniazid than will slow acetylators. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this is not proved. The slow or rapid acetylation of isoniazid is rarely important clinically, although slow inactivators tend to develop peripheral neuropathy more readily. Metabolites of isoniazid and small amounts of unaltered drug are excreted in the urine within 24 hours of administration. 

PAS is readily absorbed from the GI tract and is widely distributed throughout body fluids except cerebrospinal fluid. It penetrates tissues and reaches high concentrations in the tuberculous cavities and caseous tissue. Peak plasma levels are reached within 1 to 2 hours of drug administration, and the drug has a half-life of about an hour. PAS is primarily metabolized by hepatic acetylation. When combined with isoniazid, PAS can function as an alternative substrate and block hepatic acetylation of isoniazid, thereby increasing free isoniazid levels. Both the acetylated and unaltered drug are rapidly excreted in the urine. The concentration of PAS in urine is high and may result in crystalluria. 

Isoniazid is completely absorbed on oral administration and penetrates all tissues of the body. Peak plasma levels are reached within one hour and persists for 24 hours. It penetrates intraceUularly and diffuses into macrophages and the necrotic centres. It is metabolized in liver by acetylation and isoniazid metabolites and a small amount of unchanged drug is excreted mainly by kidney. 

Isoniazid metabolites and a small amount of unchanged drug are excreted, mainly in the urine. The dose need not be adjusted in renal failure. Dose adjustment is not well defined in patients with severe preexisting hepatic insufficiency... 

Peripheral neuropathy is observed in 10-20% of patients given dosages greater than 5 mg/kg/d, but it is infrequently seen with the standard 300-mg adult dose. Peripheral neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These may also respond to pyridoxine. 

The major routes of metabolism for isoniazid are acetylation to give acetylisoniazid, followed by hydrolysis to yield isonicotinic acid and acetylhydrazine (Fig. 7.24). The acetylation of isoniazid in human populations is genetically determined and therefore shows a bimodal distribution (see chap. 5). Thus, there are two acetylator phenotypes, termed "rapid and slow acetylators," which may be distinguished by the amount of acetylisoniazid excreted or by the plasma half-life of isoniazid. 

Factors which tend to decrease bioavailability of pyridoxine include (1) Administration of isoniazid (2) loss in cooking (estimated at 30-45%)—vitamin is water-soluble, (3) diuresis and gastrointestinal diseases (4) irradiation. Availability can be increased by stimulating intestinal bacterial production (very small amount), and storage in liver. The target tissues of Be are nervous tissue, liver, lymph nodes, and muscle tissue. Storage is by muscle phosphorylase (skeletal muscle—small amount). It is estimated that 57% of the vitamin ingested per day is excreted. The vitamin exerts only limited toxicity for humans. 

Blood urate concentrations can be increased because of reduced excretion of uric acid in patients taking ethambutol (390). This is probably enhanced by combined treatment with isoniazid and pyridoxine. Special attention should be paid when tuberculostatic drug combinations include pyrazinamide. However, severe untoward clinical effects are rare, except in patients with gout or renal insufficiency (391,392). 

Although, owing to the wide distribution of vitamin Bg in nature, clinical deficiency symptoms are seldom observed, there is little doubt that pyridoxine is essential in human nutrition. Pyridoxine is absorbed from the gastrointestinal tract and is converted to the active form pyri-doxal phosphate. Absorption is decreased in gastrointestinal diseases and also in subjects taking isoniazid (3). It is excreted in the urine as 4-pyridoxic acid (2). The metabolism of vitamin Bg in human beings has been investigated (56). 

Ethambutol [e THAM byoo tole] is bacteriostatic and specific for most strains of M- tuberculosis and M- kansasii. Resistance is not a serious problem if the drug is employed with other antituberculous agents. Ethambutol can be used in combination with pyrazinamide, isoniazid, and rifampin to treat tuberculosis. Absorbed on oral administration, ethambutol is well distributed throughout the body. Penetration into the central nervous system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion. The most important adverse effect is optic neuritis, which results in... 

Ethionamide This structural analog of isoniazid is believed not to act by the same mechanism. It is effective after oral administration, and is widely distributed throughout the body, including the CSF. Metabolism is extensive. Ethionamide [e thye on AM ide] can inhibit acetylation of isoniazid (Figure 33.7). The urine is the main route of excretion. Adverse effects that limit its use include gastric irritation, hepatotoxicity, peripheral neuropathies, and optic neuritis. Isoniazid... 

A number of features of isoniazid hepatotoxicity can be interpreted by reference to the metabolic scheme shown in Figure 16.6. First/ phenotypic slow ace ty la tors are more prone to liver damage than are rapid acetylators (Table 16.3) (30). Not only were hydrazine plasma concentrations higher in slow acetylators than in rapid acetylators treated with isoniazid for 14 days (31)/ hut, in another study/ urine excretion of hydrazine was higher in slow than in rapid acetylatorS/ whereas urine excretion of... 

Peretti E, Karlaganis G, Lauterburg BH. Increased urinary excretion of toxic hydrazino metabolites of isoniazid by slow acetylators. Effect of a slow-release preparation of isoniazid. Eur J Clin Pharmacol 1987 33 283-6. 

Morales and Lincoln (Mil) studied pyridoxine deficiency in 26 tuberculous children. Of these 20 received isoniazid therapy for various periods and clinical signs of Be deficiency were not observed. The ability to convert tryptophan to N -methylnicotinamide was used as a test for pyridoxine deficiency. Except for 1 case, all patients showed an increase in urinary N -methylnicotinamide excretion after tryptophan loading, and the authors admit the absence of pyridoxine deficiency. 

Peripheral neuropathy has been observed as a complication in tuberculosis therapy with isonicotinic acid hydrazide (isoniazid), especially when large doses have been employed (B14). This complication of isoniazid therapy has been largely eliminated by simultaneous administration of pyridoxine. These observations have prompted studies on the urinary excretion of xanthurenic acid as an index of the antipyridoxine activity of isoniazid. The excretion of an excess of vitamin Be as such... 

In a group of 10 tuberculous subjects, no modification of tryptophan metabolism was observed at the beginning of isoniazid therapy, whereas abnormal excretion of xanthurenic acid and kynurenine appeared after prolonged isoniazid treatment following a tryptophan load (R6). 

Isoniazid is a structural analogue of pyridoxine and accelerates its excretion, the principal result of which is peripheral neuropathy with numbness and tingling of the feet, motor involvement being less common. Neuropathy is more frequent in slow acetylators, malnourished people, the elderly and those with HIV infection, liver disease and alcoholism. Such patients should receive pyridoxine lOmg/d by mouth, which prevents neuropathy and does not interfere with the therapeutic effect some prefer simply to give pyridoxine to all patients. Other adverse effects include mental disturbances, incoordination, optic neuritis and convulsions. 

Thiacetazone is tuberculostatic and is used with isoniazid to inhibit the emergence of resistance to the latter drug. It is absorbed from the gastrointestinal tract, partly metabolised and partly excreted in the urine (t) 13 h). 

Isoniazid 300 mg/day orally for 7 days increased serum ethambutol concentrations at 4, 6, and 8 hours after a daily dose of 20 mg/kg the cumulative percentage dose excreted was significantly reduced at 4, 6, and 24 hours (29). In another study from the same center, ethambutol 20 mg/kg did not alter the pharmacokinetics of a single dose of isoniazid 300 mg in 10 patients with tuberculosis (30). 

Singhal KC, Rathi R, Varshney DP, Kishore K. Serum concentration and urinary excretion of ethambutol administered alone and in combination with isoniazid in patients of pulmonary tuberculosis. Indian J Physiol Pharmacol... 

After oral administration, isoniazid reaches a peak plasma concentration of 3-5 micrograms/ml within 1-2 hours. It equihbrates into all body fluids and tissues and 75-95% is excreted in the urine within 24 hours. The most important urinary metabolites are products of acetylation (acetyliso-niazid) and hydrolysis (isonicotinic acid). Isonicotinyl glycine, isonicotinyl hydrazones, and A-methylisoniazid appear in only small amounts. The rate of acetylation of isoniazid significantly alters its plasma concentrations and half-life. The mean half-Ufe of isoniazid in rapid acetyla-tors is about 70 minutes and in slow acetylators 3 hours. 

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