From the Guidelines
Isoniazid therapy leads to reduced levels of pyridoxal phosphate (vitamin B6), which primarily impairs transamination reactions in amino acid metabolism, as evidenced by the most recent study 1. When isoniazid is administered, it binds to pyridoxal phosphate, creating inactive complexes that are rapidly excreted in urine. This depletion affects numerous enzymatic reactions that require pyridoxal phosphate as a cofactor, particularly those involved in the synthesis of neurotransmitters like GABA, serotonin, and catecholamines. The most clinically significant impairment occurs in transamination reactions where amino groups are transferred between amino acids and keto acids. This metabolic disruption can manifest as peripheral neuropathy, characterized by tingling and numbness in extremities. To prevent these complications, pyridoxine (vitamin B6) supplementation at 25-50 mg daily is recommended for patients on isoniazid therapy, especially those at higher risk such as malnourished individuals, pregnant women, and those with conditions like diabetes, uremia, or alcoholism, as supported by the guidelines 1. Key points to consider include:
- Isoniazid's impact on vitamin B6 levels and the resulting effects on amino acid metabolism
- The importance of pyridoxine supplementation in preventing peripheral neuropathy and other complications
- The identification of high-risk patients who require closer monitoring and potentially higher doses of pyridoxine supplementation, as noted in 1 and 1. Overall, the evidence suggests that isoniazid therapy can lead to significant metabolic disruptions, and pyridoxine supplementation is a crucial component of therapy to mitigate these effects.
From the FDA Drug Label
Pyridoxine (vitamin B6) deficiency is sometimes observed in adults with high doses of isoniazid and is considered probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase. The metabolic reaction impaired is the tryptophan metabolism, specifically the reaction catalyzed by the enzyme apotryptophanase, which is competed with by isoniazid for pyridoxal phosphate.
- The development of reduced levels of pyridoxal phosphate is likely due to this competition.
- This can lead to pyridoxine (vitamin B6) deficiency in adults taking high doses of isoniazid 2.
From the Research
Metabolic Reactions Impaired by Isoniazid
Isoniazid develops reduced levels of pyridoxal phosphate, which is a coenzyme involved in various metabolic reactions. The impaired metabolic reactions include:
- Glutamic-oxaloacetic transaminase (GOT) activity, which is reduced due to deficiency of both the coenzyme (pyridoxal phosphate) and the apoenzyme 3
- Metabolism of protein, carbohydrates, fatty acids, and several other substances, including brain amines, which is inhibited by isoniazid 4
- Intestinal absorption of zinc, which is facilitated by picolinic acid, a metabolite of tryptophan, and is indirectly dependent on an adequate supply of vitamin B6 5
- Formation of pyridoxal phosphate, which appears to be indirectly dependent on Zn2++ which activates pyridoxal kinase 5
Enzymes Affected by Isoniazid
The enzymes affected by isoniazid include:
- Kynureninase, which is dependent on pyridoxal phosphate and is involved in the derivation of picolinic acid from tryptophan 5
- Glutamic-oxaloacetic transaminase, which is dependent on pyridoxal phosphate and is involved in the metabolism of amino acids 3
- Pyridoxal kinase, which is activated by Zn2++ and is involved in the formation of pyridoxal phosphate 5