イソニアジド-d4

Tuberculosis Treatment

Isoniazid-d4 retains the pharmacological properties of isoniazid, making it relevant in the treatment of tuberculosis (TB). The compound's mechanism involves inhibiting the synthesis of mycolic acids in the bacterial cell wall, which is critical for the survival of Mycobacterium tuberculosis.

Pharmacokinetic Studies

Isoniazid-d4 is employed as an internal standard in pharmacokinetic studies to quantify the concentration of isoniazid and its metabolites in biological samples. A study utilized liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze serum levels of isoniazid using Isoniazid-d4 as a stable isotope-labeled internal standard, enhancing the accuracy of quantification .

Translational Pharmacology

Recent research has demonstrated the potential of zebrafish larvae as a model for studying TB pharmacodynamics using Isoniazid-d4. By quantifying internal exposure and correlating it with bacterial burden, researchers established a translational model that links findings from zebrafish to human responses . This innovative approach aids in understanding drug efficacy and optimizing dosing regimens.

Bioanalytical Methods

Isoniazid-d4 has been integral in developing bioanalytical methods for measuring drug concentrations in various biological matrices. For instance, a validated assay was developed to quantify isoniazid and acetyl-isoniazid in human urine, utilizing Isoniazid-d4 to improve measurement reliability . This method underscores the importance of stable isotopes in enhancing analytical precision.

Dried Blood Spot Analysis

The application of Isoniazid-d4 in dried blood spot (DBS) analysis has been explored to assess drug stability and concentration. A study developed a UPLC-MS/MS method for measuring isoniazid concentrations from DBS samples, demonstrating the feasibility of using Isoniazid-d4 for accurate drug monitoring .

Case Studies

Target of Action

Isoniazid-d4, a deuterated form of Isoniazid, is primarily active against organisms of the genus Mycobacterium , specifically M. tuberculosis, M. bovis and M. kansasii . It is a highly specific agent, ineffective against other microorganisms .

Mode of Action

Isoniazid-d4 is a prodrug and must be activated by bacterial catalase . Specifically, activation is associated with the reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex . The antimicrobial activity of Isoniazid-d4 is selective for mycobacteria, likely due to its ability to inhibit mycolic acid synthesis , which interferes with cell wall synthesis, thereby producing a bactericidal effect . It also disrupts DNA, lipid, carbohydrate, and nicotinamide adenine dinucleotide (NAD) synthesis and/or metabolism .

Biochemical Pathways

The biochemical pathways affected by Isoniazid-d4 are primarily related to the synthesis of mycolic acids, an essential component of the bacterial cell wall . By inhibiting mycolic acid synthesis, Isoniazid-d4 interferes with cell wall synthesis, leading to a bactericidal effect . It also disrupts DNA, lipid, carbohydrate, and NAD synthesis and/or metabolism .

Pharmacokinetics

For its parent compound isoniazid, the estimated absorption rate constant (k a ), oral clearance (cl/f), and apparent volume of distribution (v 2 /f) were reported as 394 ± 044 h −1, 182 ± 245 L⋅h −1, and 568 ± 553 L, respectively . The NAT2 genotypes had different effects on the CL/F and F M .

Result of Action

The result of Isoniazid-d4 action is the inhibition of the growth of Mycobacterium species, specifically M. tuberculosis, M. bovis and M. kansasii . It is bactericidal when mycobacteria grow rapidly and bacteriostatic when they grow slowly .

Biochemical Properties

Isoniazid-d4 plays a significant role in biochemical reactions. It interacts with various enzymes, proteins, and other biomolecules. The drug’s antimicrobial activity is selective for mycobacteria, likely due to its ability to inhibit mycolic acid synthesis, which interferes with cell wall synthesis . This interaction disrupts DNA, lipid, carbohydrate, and nicotinamide adenine dinucleotide (NAD) synthesis and/or metabolism .

Cellular Effects

Isoniazid-d4 has profound effects on various types of cells and cellular processes. It influences cell function by disrupting DNA, lipid, carbohydrate, and NAD synthesis and/or metabolism . It is active against both intracellular and extracellular Mycobacterium tuberculosis .

Molecular Mechanism

The molecular mechanism of Isoniazid-d4 involves its ability to inhibit mycolic acid synthesis, which interferes with cell wall synthesis, thereby producing a bactericidal effect . It also disrupts DNA, lipid, carbohydrate, and NAD synthesis and/or metabolism .

Temporal Effects in Laboratory Settings

It is known that the organism is most susceptible to Isoniazid-d4 during its logarithmic phase of growth .

Dosage Effects in Animal Models

The effects of Isoniazid-d4 vary with different dosages in animal models. For instance, in a mouse model of pellagra-related nausea induced by feeding mice a low-niacin diet and administering Isoniazid-d4, it was observed that the drug induced pica in mice fed a low-niacin diet .

Metabolic Pathways

Isoniazid-d4 is involved in several metabolic pathways. Enzymatic acylation of Isoniazid-d4 by N-arylaminoacetyl transferases (NATs) reduces the therapeutic effectiveness of the drug . This acetylation represents a major metabolic pathway for Isoniazid-d4 in human beings .

Synthetic Routes and Reaction Conditions: The synthesis of isoniazid-d4 typically involves the introduction of deuterium atoms into the isoniazid molecule. One common method is the catalytic exchange of hydrogen with deuterium in the presence of a deuterium source such as deuterium oxide (D2O). The reaction is usually carried out under controlled conditions to ensure the selective incorporation of deuterium atoms.

Industrial Production Methods: Industrial production of isoniazid-d4 follows similar principles but on a larger scale. The process involves the use of specialized reactors and catalysts to achieve high yields and purity. The reaction conditions, such as temperature, pressure, and the concentration of deuterium source, are optimized to maximize the efficiency of the deuteration process.

Types of Reactions: Isoniazid-d4 undergoes various chemical reactions similar to its non-deuterated counterpart. These include:

Oxidation: Isoniazid-d4 can be oxidized to form isonicotinic acid.

Reduction: It can be reduced to form hydrazine derivatives.

Substitution: The compound can undergo nucleophilic substitution reactions, particularly at the hydrazide group.

Common Reagents and Conditions:

Oxidation: Common oxidizing agents include potassium permanganate and hydrogen peroxide.

Reduction: Reducing agents such as sodium borohydride or lithium aluminum hydride are used.

Substitution: Nucleophiles like amines or thiols can be used under basic conditions.

Major Products Formed:

Oxidation: Isonicotinic acid.

Reduction: Hydrazine derivatives.

Substitution: Various substituted hydrazides.

Isoniazid: The non-deuterated form, widely used in tuberculosis treatment.

Rifampicin: Another first-line antituberculosis drug with a different mechanism of action.

Ethambutol: Used in combination with isoniazid for tuberculosis treatment.

Uniqueness of Isoniazid-d4: The incorporation of deuterium atoms in isoniazid-d4 provides unique advantages in research, such as improved stability and the ability to trace metabolic pathways more accurately. This makes it a valuable tool in both clinical and laboratory settings, offering insights that are not possible with non-deuterated compounds.

Isoniazid-d4 (INH-d4) is a deuterated analog of isoniazid, a first-line drug used in the treatment of tuberculosis (TB). The introduction of deuterium in the molecular structure alters its pharmacokinetic and metabolic properties, potentially enhancing its therapeutic efficacy and reducing toxicity. This article explores the biological activity of INH-d4, focusing on its pharmacodynamics, pharmacokinetics, and potential mechanisms of action.

Chemical Structure and Properties

Isoniazid-d4 has the chemical formula $C_6H_7D_4N_3O$ and is characterized by the substitution of four hydrogen atoms with deuterium. This modification can influence the drug's metabolism and interaction with biological systems.

Pharmacodynamics

• Mechanism of Action :
  • Isoniazid functions as a prodrug that requires activation by the KatG enzyme in Mycobacterium tuberculosis. The activated form inhibits the synthesis of mycolic acids, essential components of the bacterial cell wall, leading to cell death .
  • INH-d4's deuteration may enhance its stability against metabolic degradation, thereby prolonging its action against TB bacteria .
• Histone Modification :
  • Recent studies have shown that isoniazid induces unique histone modifications, specifically isonicotinylation (K inic), which may play a role in epigenetic regulation. This modification relaxes chromatin structure and promotes gene transcription, impacting cellular responses to treatment .

Pharmacokinetics

Pharmacokinetic parameters are crucial for understanding the efficacy and safety profile of INH-d4. The following table summarizes key pharmacokinetic data for isoniazid and its deuterated form:

Note : TBD indicates that specific data for INH-d4 is still under investigation or not available in current literature.

Case Studies and Research Findings

• Metabolic Stability :
  • A study demonstrated that INH-d4 showed improved metabolic stability compared to standard isoniazid, leading to sustained therapeutic levels in plasma . This suggests that INH-d4 could potentially reduce dosing frequency and improve patient compliance.
• Toxicity Profile :
  • Research indicates that deuterated compounds often exhibit reduced toxicity due to slower metabolism and lower formation of toxic metabolites. Preliminary findings suggest that INH-d4 may have a more favorable safety profile than conventional isoniazid .
• In Vivo Efficacy :
  • Animal studies have shown that INH-d4 exhibits comparable or enhanced antibacterial activity against Mycobacterium tuberculosis compared to traditional formulations. This efficacy is attributed to both its pharmacokinetic advantages and its ability to induce favorable histone modifications .