Isoniazid distribution

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. (In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellu-larly.) Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation, the rate of which is genetically controlled and shows a characteristic distribution in different ethnic groups (fast vs. slow acetylators). Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin Be (pyridoxine) hepatitis, jaundice. 

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. 

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. 

An interesting example of racial differences in drug conversion is seen in the metabolism of the antitubercular, isoniazid. It is inactivated by an acetylation reaction. Slow acetylation leads to toxicity (lupus, drowsiness, nausea, cyanosis). Free isoniazid also inhibits the action of phenytoin (an anticonvulsive) and results in phenytoin toxicity. Normal acetylation has a half-life of 45-80 minutes while a "slow acetylator" shows a 140-200 min half-life. The U.S. population shows a 50/50 distribution of "slow" versus "fast" acetylators. 44-55% of American Causasians and blacks are "slow". 

Figure 5.21 Frequency distribution for isoniazid acetylation. The acetylated metabolite (acetylisoniazid) and total isoniazid (acid labile isoniazid) were measured in the urine. Source From Ref. 27.

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. 

Genetic polymorphism in drug metabolism. The graph shows the distribution of plasma concentrations of isoniazid in 267 individuals 6 hours after an oral dose of 9.8 mg/kg. This distribution is clearly bimodal. Individuals with a plasma concentration greater than 2.5 mg/mL at 6 hours are considered slow acetylators. (Redrawn, with permission, from Evans DAP, Manley KA, McKusick VA Genetic control of isoniazid metabolism in man. Br Med J 1960 2 485.)... 

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). 

Data with a polymodal distribution If we give a series of patients a standard oral dose of the anti-tuberculosis drug isoniazid, obtain a blood sample from each individual 6 h later and determine the isoniazid concentrations of those samples, the results will probably look like Figure 3.1. The data are bimodal, because the metabolism of isoniazid is genetically controlled and we all fall into one of two groups - fast or slow metabolizers. The fast metabolizers form the cluster at the low end of the concentration scale and the slow metabolizers form a distinct group with higher levels. 

Bimodal distribution of isoniazid half-lives caused by rapid and slow acetylation of drug. 

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... 

Para-aminosalicylic and para-minobenzoic acids are considered specific substrates for human NAT1, and sulfamethazine, isoniazid, procainamide and dapsone are considered specific substrates for human NAT2 (Butcher 2002). NAT1 is considered as ubiquitously distributed in the body, whereas NAT2 is expressed in liver and intestinal mucosa. 

The distribution is clearly bimodal (which means, it has two separate peaks). People with a plasma level of more than 2.5 mg/1 are deemed slow acetylators . This is actually a genetic trait that follows Mendelian inheritance, and it is obviously important for the individual adjustment of isoniazid dosage. It is the classical but by no means single example of genetic variation in drug metabolism. The study of phenomena of this type is called pharmacogenetics , and there actually is a scientific journal of that name. 

Figure 2.30. Metabolism of isoniazid. a Acetylation, b Hydrolysis of the acetyl conjugate leads to liver toxicity, c Distribution of acetylation rates in the population.

A 52-year-old man developed pellagra with a classical photosensitive distribution after taking isoniazid for... 

TABLE 5.16 Acetylatorphenotype distribution in various ethnic groups (INH, Isoniazid SMZ, Sulphamethazine)... 

NAT2 detoxifies numerous drugs. The acetylation of isoniazid (INH) is shown in Figure 8.32. NAT2 is expressed mostly in the liver, intestinal epithelial cells, and colon. In contrast, NATI appears to metabolize fewer drug substrates even though it exhibits a more widespread tissue distribution. Para-aminobenzylglutamate... 

The discovery of polymorphic N-acetylation was linked to observations on the safety, metabolism, and pharmacokinetics of the antitubercular drug, isoniazid. When urinary excretion of isoniazid was evaluated in identical twins, fraternal twins, and unrelated subjects, the variability in its excretion depended upon genetic similarity. Ultimately, in a classic experiment by Evans and colleagues that measured the plasma isoniazid concentration in subjects who had taken a single 10 mg/kg dose of isoniazid, a clear polymorphic frequency distribution was revealed with an antimode of 2.5 ug/mL. Thus, two acetylator phenotypes were identified, and the slow acetylator phenotype had a frequency of 52%, and was an autosomal recessive trait. The slow acetylator phenotype, if treated with isoniazid (INH) is at increased risk of INH-induced arthralgias, neuropathy, and hepatotoxicity. 

ABSORPTION, DISTRIBUTION, AND EXCRETION Isoniazid is readily absorbed after oral or parenteral administration. Isoniazid diffuses readily into aU body fluids and cells. The drug achieves significant quantities in pleural and ascitic fluids concentrations in the cerebrospinal fluid (CSF) with inflamed meninges are similar to those in the plasma. Isoniazid penetrates well into caseous material and persists in therapeutic concentrations. 

---