Amino acid replacements in the NADH binding site of InhA apparently result in INH resistance by preventing the inhibition of mycolic acid biosynthesis, which the bacterium uses in its cell wall. Mutations in the katG gene make the enzyme catalase peroxidase unable to convert INH to its biologically active form. Hence, INH is ineffective and the bacterium is resistant. The discovery of new molecular targets is essential to overcome drug-resistance problems.In some TB bacteria, the acquisition of these mutations can be explained by other mutations in the DNA recombination, recognition and repair machinery. Mutations in these genes allow the bacteria to have a higher overall mutation rate and to accumulate mutations that cause drug resistance more quickly. Extensively drug-resistant TB
MDR-TB can become resistant to the major second-line TB drug groups: fluoroquinolones (moxifloxacin, ofloxacin) and injectable aminoglycoside or polypeptide drugs (amikacin, capreomycin, kanamycin). When MDR-TB is resistant to at least one drug from each group, it is classified as extensively drug-resistant tuberculosis (XDR-TB).WHO has revised the definitions of pre-XDR-TB and XDR-TB in 2021 as following:Pre-XDR-TB: TB caused by Mycobacterium tuberculosis (M.tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone. XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone and at least one additional Group A drug.
Interactions
As temozolomide is not metabolized in the liver and has a low affinity to plasma proteins, it is expected to have a low potential for interactions. An analysis of patient data showed no interactions with a range of other drugs; the exception is valproic acid, which slightly slows down temozolomide elimination from the body. Combining the drug with other myelosuppressants may increase the risk of myelosuppression. Pharmacology
Mechanism of action
The therapeutic benefit of temozolomide depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues. This methylation damages the DNA and triggers the death of tumor cells. However, some tumor cells are able to repair this type of DNA damage, and therefore diminish the therapeutic efficacy of temozolomide, by expressing a protein O6-alkylguanine DNA alkyltransferase (AGT) encoded in humans by the O-6-methylguanine-DNA methyltransferase (MGMT) gene. In some tumors, epigenetic silencing of the MGMT gene prevents the synthesis of this enzyme, and as a consequence such tumors are more sensitive to killing by temozolomide. Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide. Pharmacokinetics
Temozolomide is quickly and almost completely absorbed from the gut, and readily penetrates the blood–brain barrier; the concentration in the cerebrospinal fluid is 30% of the concentration in the blood plasma. Intake with food decreases maximal plasma concentrations by 33% and the area under the curve by 9%. Only 15% (10–20%) of the substance are bound to blood plasma proteins.