Clarithromycin

Binding to the 23S Ribosomal RNA (rRNA) 50S Subunit

This compound, like other macrolide antibiotics, binds reversibly to the 50S ribosomal subunit of susceptible bacteria. wikipedia.orgpatsnap.comdrugbank.comdrugbank.com The specific binding site is located on the 23S ribosomal RNA (rRNA), a key component of the 50S subunit. wikipedia.orgpatsnap.comdrugbank.commdpi.com This interaction occurs within the nascent peptide exit tunnel, a channel through which newly synthesized polypeptides emerge from the ribosome. mdpi.comnih.gov The binding site is near the peptidyl transferase center (PTC), the catalytic site responsible for peptide bond formation. patsnap.commdpi.com The macrolide binding site is primarily composed of RNA, with key interactions occurring in domain V and domain II (specifically helix 35) of the 23S rRNA. nih.gov Mutations in residues like A2058 and A2059 (using Escherichia coli numbering) in domain V are known to confer resistance to macrolides, suggesting their direct involvement in drug binding. nih.govcertest.esresearchgate.net

Disruption of Ribosomal Translocation and Protein Elongation

A key consequence of this compound binding to the 50S subunit is the disruption of ribosomal translocation. patsnap.comdrugbank.com Translocation is the essential step in protein synthesis where the ribosome moves along the messenger RNA (mRNA) molecule, allowing for the sequential addition of amino acids to the growing peptide chain. patsnap.com By binding within the peptide exit tunnel, this compound physically obstructs this movement, effectively halting the elongation of the polypeptide chain. patsnap.commdpi.comsigmaaldrich.com This interruption prevents the synthesis of complete, functional proteins required for bacterial growth and survival. patsnap.com

Kinetic Analysis of this compound-Ribosome Binding

Kinetic studies have provided insights into the interaction between this compound and bacterial ribosomes. This compound binds tightly to bacterial ribosomes. nih.govcapes.gov.br Studies using Helicobacter pylori ribosomes, for example, have shown dissociation constants (Kd) in the nanomolar range, indicating a strong binding affinity. nih.govcapes.gov.br The binding process can involve a rapid initial interaction followed by a slower isomerization to a more stable complex. nih.govresearchgate.net The dissociation rate constants for this compound from ribosomes can be very slow, contributing to its sustained inhibitory effect. nih.govcapes.gov.brresearchgate.net

Here is a table summarizing some reported dissociation constants for macrolides binding to E. coli ribosomes:

Note: Data derived from a study using a cell-free system from Escherichia coli. nih.gov

For Helicobacter pylori ribosomes, the binding is even tighter, with Kd values around 0.2 nM for this compound, erythromycin, and 14-hydroxythis compound. nih.govcapes.gov.br The dissociation rate constants from H. pylori ribosomes are significantly slower compared to those from other gram-negative bacteria. nih.govcapes.gov.br

Structural and Conformational Studies of Ribosome-Bound this compound

Structural studies, including cryo-electron microscopy (cryo-EM), have provided detailed views of how this compound interacts with the ribosome. tandfonline.comfigshare.com These studies show this compound binding within the nascent peptide exit tunnel. mdpi.comtandfonline.comfigshare.com this compound adopts a specific "folded-in" conformation within the tunnel, distinct from some larger macrolides. mdpi.com The lactone ring of this compound is positioned nearly perpendicular to the tunnel wall, and its cladinose sugar moiety forms specific interactions that stabilize its binding to the ribosome. mdpi.com These structural details help explain the drug's ability to block the tunnel and inhibit protein synthesis. mdpi.com Studies on Mycobacterium tuberculosis ribosomes bound with this compound have revealed dynamic interactions and specific contacts, including C-H hydrogen bonds and pi interactions, that contribute to enhanced binding affinity. tandfonline.comfigshare.com

Point Mutations in the 23S rRNA Gene

Point mutations in domain V of the 23S rRNA gene are the most common mechanism of this compound resistance, particularly in Helicobacter pylori. These mutations alter the binding site of this compound on the ribosome, reducing its affinity and thus its inhibitory effect. turkjgastroenterol.orgmdpi.comptbioch.edu.plmdpi.comseq.eskoreascience.krasm.org

In Helicobacter pylori, the most prevalent point mutations associated with this compound resistance are located at positions 2142 and 2143 in the 23S rRNA gene (using H. pylori numbering, which corresponds to positions 2058 and 2059 in Escherichia coli numbering). ptbioch.edu.plseq.es Specifically, the A2143G, A2142G, and A2142C mutations are frequently detected in this compound-resistant H. pylori isolates worldwide. turkjgastroenterol.orgmdpi.comptbioch.edu.plseq.esasm.org

Studies have shown varying prevalence rates of these mutations in different geographical regions. For instance, in a study in Turkey, the majority of mutations were A2143G (41.3%), followed by A2142G (30.4%) and A2142C (15.2%) among resistant isolates. turkjgastroenterol.org In Korean patients, A2143G was a frequently observed mutation in primary this compound-resistant isolates. koreascience.kr Research in Brazil indicated that either the A2142G or the A2143G mutation was present in a high percentage of resistant strains, with A2142G being the majority (82.7%). nih.gov

The specific mutation can influence the level of resistance. Some studies suggest that the A2142G mutation may be associated with higher minimum inhibitory concentration (MIC) values compared to A2143G mutations in H. pylori. ptbioch.edu.plnih.gov For example, one study reported average MIC values of 6 mg/L for A2143G mutants and 30 mg/L for A2142G mutants. ptbioch.edu.pl

Here is a table summarizing the prevalence of key mutations in a study from Turkey:

Data compiled from search result turkjgastroenterol.org.

The A2058G and A2059 mutations (using E. coli numbering) in the rrl gene, which encodes the 23S rRNA, are well-established mechanisms of acquired macrolide resistance in various bacterial species, including mycobacteria and streptococci. asm.orgnih.govresearchgate.netfrontiersin.org These mutations are located in the peptidyltransferase domain of the 23S rRNA and directly interfere with macrolide binding. nih.govresearchgate.netfrontiersin.org

In Streptococcus pneumoniae, for example, the A2058G or A2058U mutations can confer high-level resistance to 14- and 15-membered macrolides, including this compound. asm.org The A2059G mutation, while also contributing to resistance, may result in a lower level of resistance compared to A2058 alterations. asm.org These mutations disrupt critical contact sites involved in macrolide binding to the ribosome. asm.orgresearchgate.net

The T2182C mutation in the 23S rRNA gene of Helicobacter pylori has been observed in some this compound-resistant isolates. turkjgastroenterol.orgmdpi.comkoreascience.krnih.govresearchgate.netscielo.br However, its clinical significance and direct association with this compound resistance have been debated. mdpi.comnih.gov Some studies have detected the T2182C mutation in both this compound-susceptible and resistant strains, suggesting it may not independently confer resistance or its role might be more complex. nih.gov

One study in Korean patients found T2182C in primary this compound-resistant isolates, and it was frequently observed in combination with A2143G in secondary resistant isolates. koreascience.kr While some initial reports suggested T2182C conferred resistance, further investigation, including the analysis of mixed bacterial populations, indicated that the resistance might have been attributable to co-occurring known resistance mutations like A2143G. nih.gov Despite the controversy, the T2182C mutation is one of the mutations detected in the 23S rRNA gene of H. pylori. mdpi.comscielo.brloinc.org

Beyond the well-characterized A2142 and A2143 mutations in H. pylori, other point mutations in the 23S rRNA gene have been identified and are being investigated for their role in this compound resistance. turkjgastroenterol.orgmdpi.comnih.gov These novel mutations can occur in various regions of the 23S rRNA gene. turkjgastroenterol.orgmdpi.comscielo.brnih.govasm.org

Examples of other mutations detected in H. pylori 23S rRNA include T2188C, G1949A, G1940A, and C1944T. turkjgastroenterol.org A T-to-C transition at position 2717 (using H. pylori numbering) has also been reported to confer a low level of this compound resistance. asm.org Additionally, mutations at positions such as C2611A have been associated with low-level this compound resistance in H. pylori. nih.gov

The significance of these novel mutations can vary. Some may confer low-level resistance, while others might contribute to resistance in conjunction with other genetic alterations. nih.govnih.gov Research utilizing techniques like next-generation sequencing continues to identify new potential resistance-associated mutations in the 23S rRNA gene and other genes. mdpi.comnih.gov

Role of T2182C Mutation in 23S rRNA

erm Gene-Mediated Ribosomal Methylation

Another significant mechanism of macrolide resistance, including resistance to this compound, is the enzymatic methylation of a specific adenine residue (A2058, E. coli numbering) in domain V of the 23S rRNA. mdpi.comkoreascience.krnih.govresearchgate.netscielo.brnih.govoup.comfrontiersin.org This modification is mediated by ribosomal methyltransferases encoded by erm (erythromycin ribosome methylation) genes. nih.govoup.comfrontiersin.orgresearchgate.net

Methylation of A2058 prevents or reduces the binding of macrolides to the ribosome, conferring resistance. nih.govoup.comfrontiersin.org The level of resistance can depend on whether the adenine is monomethylated or dimethylated. frontiersin.org This mechanism often results in the MLSB phenotype, which is cross-resistance to macrolides, lincosamides, and streptogramin B antibiotics. asm.orgnih.govfrontiersin.orgmjima.org

erm genes are found in various pathogenic bacteria, and different erm genes (e.g., erm(A), erm(B), erm(C), erm(F), erm(41), erm(55)) are prevalent in different species. nih.govoup.comresearchgate.netmjima.org For instance, erm(B) is commonly found in streptococci, while erm(A), erm(B), or erm(C) are found in staphylococci. nih.govmjima.org In some organisms like Mycobacterium abscessus, the erm(41) gene is associated with inducible this compound resistance upon prolonged exposure to the antibiotic. nih.govfrontiersin.orgoup.com The expression of many erm genes is inducible by macrolides. nih.govoup.com

Here is a table summarizing key resistance mechanisms:

erm(B) Gene and its Distribution

The erm(B) gene is another important macrolide resistance determinant, widely distributed among various Gram-positive bacteria, including Enterococcus, Streptococcus, and Staphylococcus species. frontiersin.org It encodes an rRNA methylase that mediates target-site modification by methylating an adenine residue in the 23S rRNA, similar to erm(41). frontiersin.org This modification leads to cross-resistance not only to macrolides but also to lincosamides and streptogramin B antibiotics, a phenotype known as MLSB resistance. frontiersin.orgresearchgate.netmjima.org

While primarily found in Gram-positive bacteria, the erm(B) gene has also been identified in some Gram-negative species, such as Campylobacter coli and Campylobacter jejuni, often located within genomic islands or conjugative transposons, highlighting the potential for horizontal gene transfer. frontiersin.orgasm.org Studies have shown that the presence of erm(B) is associated with high levels of resistance to erythromycin and other macrolides, including this compound. mjima.orgasm.orgnih.gov

A study investigating macrolide resistance in Streptococcus pneumoniae found erm(B) in a significant percentage of isolates, often associated with high minimum inhibitory concentrations (MICs) of this compound. mjima.orgnih.gov The prevalence of erm(B) can vary geographically. mjima.org

Novel Plasmid-Mediated erm(55)P Gene

A novel plasmid-mediated erm gene, designated erm(55)P, has been identified in Mycobacterium chelonae, another rapidly growing mycobacterium. researchgate.netnih.govnih.gov This discovery is significant as plasmid-mediated macrolide resistance had not been previously described in nontuberculous mycobacteria (NTM). researchgate.netnih.gov The erm(55)P gene is located on a putative 137-kb conjugative plasmid, pMchErm55. researchgate.netnih.govnih.gov

The erm(55)P gene encodes a 23S rRNA methylase that confers high-level inducible this compound resistance. researchgate.netnih.govasm.org This resistance is typically detected with extended incubation susceptibility testing. researchgate.netasm.org The erm(55)P gene shares less than 65% amino acid identity with previously described RGM erm genes. researchgate.netnih.govnih.gov

The presence of erm(55)P has also been observed in public databases from other emerging pathogenic pigmented RGM species, such as Mycobacterium iranicum and Mycobacterium obuense, suggesting potential horizontal spread via homologous plasmids like pMchErm55. researchgate.netnih.govasm.org Experimental evidence has confirmed that erm(55)P, along with chromosomal variants erm(55)C and erm(55)T, confers resistance to this compound. asm.org

Deletions and Point Mutations (e.g., T28C) in erm(41) and Susceptibility Reversion

While a functional erm(41) gene is associated with inducible macrolide resistance in MABC, specific genetic alterations within this gene can lead to a reversion to this compound susceptibility. oup.comfrontiersin.orgnih.gov Two such alterations are particularly notable: a 274 bp deletion and a T28C point mutation. oup.comfrontiersin.orgnih.gov

A significant proportion of susceptible MABC isolates, particularly M. abscessus subsp. massiliense, harbor deletions in the erm(41) gene, rendering the encoded methylase inactive and the bacteria susceptible to macrolides. oup.comasm.orgatsjournals.orgfrontiersin.orgoup.comfrontiersin.orgnih.gov

The T28C point mutation (a change from Thymidine to Cytosine at position 28) in the erm(41) gene is another key alteration associated with macrolide susceptibility. oup.comoup.comfrontiersin.orgnih.govresearchgate.net This mutation results in an amino acid change (Tryptophan to Arginine at codon 10) that leads to a non-functional Erm(41) protein. frontiersin.orgresearchgate.net Isolates carrying the C28 polymorphism are typically susceptible to this compound. oup.comfrontiersin.orgresearchgate.net Studies have shown that susceptible isolates without large deletions often carry this T28C point mutation. oup.comnih.gov

The presence of these deletions or the T28C mutation in erm(41) can be used as molecular markers to predict this compound susceptibility in MABC isolates. oup.comnih.gov

Efflux Pump Systems

Efflux pump systems are another significant mechanism contributing to this compound resistance in various pathogenic microorganisms, including Mycobacterium abscessus and Helicobacter pylori. oup.commdpi.comnih.govmicrobiologyresearch.orgdovepress.comnih.govnih.govmdpi.comcapes.gov.brfrontiersin.org These pumps are membrane proteins that actively transport antibiotic compounds out of the bacterial cell, thereby reducing the intracellular concentration of the drug below inhibitory levels. microbiologyresearch.orgfrontiersin.org

Overexpression of Efflux Pumps

Overexpression of efflux pumps is a common mechanism leading to increased antibiotic resistance, including resistance to this compound. oup.commdpi.comdovepress.comnih.govmdpi.comfrontiersin.orgscielo.brresearchgate.net Increased expression of the genes encoding these pumps results in a higher number of functional efflux pumps in the bacterial membrane, leading to more efficient expulsion of the antibiotic. dovepress.comnih.govfrontiersin.org

Studies in Mycobacterium abscessus have shown that overexpression of specific efflux pump genes, such as MAB_2355c, MAB_1409c, and MAB_1846, correlates with increased this compound resistance. dovepress.comnih.gov Efflux activity can contribute significantly to this compound resistance, even in isolates with the inducible resistance-conferring T28 erm(41) sequevar. nih.govmdpi.comresearchgate.net Inhibition of efflux pumps using specific inhibitors has been shown to decrease the MIC of this compound, highlighting their role in resistance. nih.govdovepress.comnih.govnih.govmdpi.comcapes.gov.br

In Helicobacter pylori, overexpression of efflux pumps is also implicated in this compound resistance, often acting in synergy with ribosomal mutations. microbiologyresearch.orgnih.govcapes.gov.brnih.gov

Role of hefABC, hefDEF, hefGHI Gene Families in H. pylori

In Helicobacter pylori, several gene families encoding Resistance-Nodulation-Cell Division (RND) family efflux pumps play a role in antibiotic resistance, including resistance to this compound. mdpi.commicrobiologyresearch.orgfrontiersin.orgrevistagastroenterologiamexico.orgresearchgate.net The prominent RND efflux systems in H. pylori include those encoded by the hefABC, hefDEF (also referred to as cznABC), and hefGHI (also referred to as czcAB-crdB) operons. microbiologyresearch.orgrevistagastroenterologiamexico.org

The hefABC operon is considered most similar to known multidrug efflux pumps. microbiologyresearch.org Studies have indicated the involvement of the HefABC pump in resistance to various antibiotics, including this compound. mdpi.comresearchgate.net Overexpression of hefABC has been observed in multidrug-resistant H. pylori strains. mdpi.comresearchgate.net

P-glycoprotein Efflux Transporter Inhibition

P-glycoprotein (P-gp), an efflux membrane transporter belonging to the ATP-binding cassette (ABC) transporter superfamily, is widely distributed throughout the body and plays a role in extruding various compounds, including some therapeutic agents, out of cells. nih.govscielo.br While primarily recognized for its role in mammalian multidrug resistance, particularly in cancer cells, efflux pumps are also a common mechanism of resistance in microorganisms. nih.govhksmp.com P-gp has been identified in both Gram-negative and Gram-positive microbes and is considered a major transporter responsible for multidrug resistance. hksmp.com

Studies have demonstrated that macrolide antibiotics, including this compound, can inhibit P-gp-mediated efflux of certain substrates, such as digoxin, potentially leading to increased systemic concentrations of those co-administered drugs. mdpi.comresearchgate.net This suggests that this compound can act as a P-gp inhibitor. mdpi.com However, the direct role of P-gp in mediating this compound efflux in bacteria as a primary resistance mechanism requires further clarification. nih.gov

Other Resistance-Associated Genes and Mutations (e.g., infB, rpl22, TauE/SafE, DUF874)

While point mutations in the 23S rRNA gene, particularly in domain V, are the most common mechanism of this compound resistance, other genes and mutations have also been implicated. nih.govresearchgate.netnih.govmdpi.com

Research using next-generation sequencing has identified novel gene mutations potentially related to this compound resistance in Helicobacter pylori. Mutations in the infB and rpl22 genes have been discovered and are suggested to exert synergistic effects with 23S rRNA mutations, resulting in higher minimum inhibitory concentrations (MICs). nih.govmdpi.comresearchgate.netnih.gov Transformants containing single mutations in infB or rpl22 showed low MICs, while those with double mutations (in 23S rRNA and infB or rpl22) exhibited significantly higher MICs. researchgate.net

Furthermore, mutations in genes encoding for the sulfite exporter TauE/SafE family protein and a DUF874 family protein have been considered as potentially linked to this compound resistance or cross-resistance in H. pylori. researchgate.netresearchgate.netnih.gov These mutations were identified in laboratory-induced resistant strains and highlight potential targets for further investigation. researchgate.netresearchgate.netnih.gov

Inducible vs. Constitutive Resistance

This compound resistance can manifest as either inducible or constitutive, particularly in organisms like the Mycobacterium abscessus complex. nih.govscilit.comd-nb.infonih.govresearchgate.net Constitutive resistance is typically associated with spontaneous point mutations, often in the rrl gene (encoding for 23S rRNA), which are selected for during macrolide therapy. nih.gov These mutations lead to high-level resistance values observed early in in vitro susceptibility testing, such as at 3 days of culture. nih.govd-nb.info

Inducible resistance, on the other hand, is linked to the presence of a functional erm(41) gene. nih.govscilit.comd-nb.info This gene encodes an erythromycin ribosomal methyltransferase that modifies the ribosome, reducing this compound binding. d-nb.info Inducible resistance is characterized by lower initial resistance values that increase significantly after extended exposure to the antibiotic, typically becoming apparent at later time points like 7 or even 14 days in in vitro susceptibility testing. nih.govd-nb.info The erm(41) gene sequence can vary between M. abscessus subspecies, with specific alleles (e.g., T28) being associated with inducible resistance, while others (e.g., C28 or truncated genes) may lead to susceptibility. nih.govd-nb.info

Minimum Inhibitory Concentration (MIC) Values and Resistance Correlation

Minimum Inhibitory Concentration (MIC) values are a direct measure of the phenotypic resistance of a bacterial isolate to an antibiotic. For this compound, elevated MIC values are strongly correlated with resistance. researchgate.netnih.govd-nb.infoCurrent time information in Monterrey, MX.nih.govf1000research.comdovepress.comresearchgate.net

Studies on Helicobacter pylori have consistently shown that this compound-resistant strains exhibit significantly higher MICs compared to susceptible strains. researchgate.netnih.govf1000research.comdovepress.comresearchgate.net The presence of specific mutations, particularly in the 23S rRNA gene (such as A2142G and A2143G), is strongly associated with high this compound MICs. nih.govresearchgate.netnih.govmdpi.comresearchgate.netdovepress.comresearchgate.net For example, studies have shown that the majority of this compound-resistant H. pylori isolates have MICs ranging from 2 μg/mL to 16 μg/mL or higher, based on established breakpoints. nih.govf1000research.comdovepress.com

In Mycobacterium abscessus, the distinction between inducible and constitutive resistance is also reflected in MIC values over time. Isolates with constitutive resistance show high MICs at early time points (e.g., 3 days), while those with inducible resistance demonstrate increasing MICs over extended incubation periods (e.g., 7 to 14 days). nih.govd-nb.info Susceptibility testing guidelines often require extended incubation to accurately detect inducible resistance. d-nb.info

Impact on Neutrophil and Macrophage Function

Inhibition of NF-κB Activation

Nuclear Factor-kappa B (NF-κB) is a critical transcription factor involved in the regulation of numerous genes, including those encoding pro-inflammatory cytokines, chemokines, and adhesion molecules. Activation of NF-κB plays a central role in inflammatory responses. Research indicates that this compound can inhibit the activation of NF-κB in various cell types relevant to inflammatory diseases, such as airway epithelial cells and fibroblasts. asm.orgatsjournals.orgresearchgate.netatsjournals.orgnih.gov

Studies have shown that this compound dose-dependently reduced the expression of NF-κB in human adenoidal fibroblasts. asm.org In human bronchial epithelial cells, this compound inhibited the activation of NF-κB induced by various stimuli. asm.orgatsjournals.org This inhibition of NF-κB activation is thought to contribute to the observed reduction in the production of pro-inflammatory mediators like Interleukin-8 (IL-8). asm.orgnih.gov The mechanism may involve interference with upstream signaling pathways, such as the Extracellular signal-regulated kinase (ERK) pathway, which can influence NF-κB activity. researchgate.netatsjournals.orgnii.ac.jp

Reduction of Mucus Production (e.g., Muc5ac)

Excessive mucus production and hypersecretion are common features of chronic inflammatory airway diseases, contributing to airway obstruction and impaired clearance. This compound has been demonstrated to reduce mucus production, specifically by inhibiting the expression of MUC5AC, a major gel-forming mucin in the airways. atsjournals.orgresearchgate.netatsjournals.orgnii.ac.jpmdpi.comelsevier.es

Studies using human nasal epithelial cells and bronchial epithelial cells have shown that this compound effectively inhibits the expression of MUC5AC. atsjournals.orgatsjournals.orgnii.ac.jpmdpi.com For instance, this compound significantly decreased MUC5AC mRNA expression and protein secretion induced by Interleukin-13 (IL-13), a key cytokine involved in mucus hypersecretion in conditions like asthma. atsjournals.orgatsjournals.org This effect is linked to the ability of this compound to inhibit signaling pathways such as NF-κB and ERK, which are involved in the regulation of MUC5AC expression. atsjournals.orgresearchgate.netatsjournals.orgnii.ac.jp Animal models of inflammatory airway disease have also shown that macrolides, including this compound, can inhibit Muc5ac expression. mdpi.com

Improved Mucociliary Transport

Mucociliary transport is a crucial defense mechanism of the respiratory tract, responsible for clearing inhaled particles, pathogens, and excess mucus. Impaired mucociliary clearance contributes to the pathogenesis of chronic airway diseases. This compound has been shown to improve mucociliary transportability and alter the rheological properties of mucus, facilitating its clearance. mdpi.comelsevier.esresearchgate.netnih.gov

In patients with acute purulent rhinitis, this compound treatment for two weeks increased mucociliary transportability and reduced secretion volume. mdpi.comresearchgate.netnih.gov Studies in patients with chronic rhinosinusitis have also reported that this compound treatment significantly reduced mucus viscosity and nasal clearance time. mdpi.comresearchgate.net These effects contribute to improved clearance of secretions from the airways and sinuses.

Absorption and Bioavailability Studies

This compound is rapidly absorbed from the gastrointestinal tract after oral administration. biomedres.usnih.govnih.gov Unlike erythromycin, this compound is acid-stable, which contributes to its improved oral bioavailability. nih.govwikipedia.org Studies have shown that food can enhance the absorption and bioavailability of this compound, increasing it from approximately 55% to 70%. nih.gov The bioavailability of this compound after oral administration of a 250 mg tablet is approximately 50%. who.int Peak serum concentrations are typically reached within 2 hours after dosing. biomedres.usnih.govwho.int Steady-state peak serum concentrations range from 1.0 to 1.5 mg/L after a 250 mg twice-daily dose and 2.0 to 3.0 mg/L after a 500 mg twice-daily dose. nih.gov

Distribution in Tissues and Cells

This compound is widely distributed throughout the body and achieves higher concentrations in tissues compared to serum. biomedres.usnih.govnih.govnih.gov This high tissue affinity is a notable characteristic of this compound. asm.org It diffuses extensively into various tissues and phagocytes, including saliva, sputum, lung tissue, epithelial lining fluid, alveolar macrophages, neutrophils, tonsils, and nasal mucosa. nih.gov Due to its high concentration in phagocytes, this compound is actively transported to the site of infection. wikipedia.org During active phagocytosis, significant concentrations of this compound are released. wikipedia.org Tissue concentrations can exceed plasma concentrations by more than 10 times. wikipedia.org Highest concentrations have been observed in the liver, lung tissue, and stool. wikipedia.org

Studies have provided specific data on tissue concentrations:

In tonsils, mean concentrations of this compound and its active metabolite 4 hours post-dose were 5.3 and 3.1 mg/kg, respectively, and 12 hours post-dose were 2.1 and 1.2 mg/kg. nih.gov

In nasal mucosa, parent and metabolite concentrations 4 hours post-dose were 5.9 and 3.2 mg/kg, respectively, and 12 hours post-dose were 2.2 and 1.5 mg/kg. nih.gov

this compound and its active metabolite reach similar concentrations in serum and sputum. biomedres.us

this compound achieves higher concentrations in periodontal tissue, epithelial lining fluid, and macrophages than in plasma. biomedres.us

this compound and 14-hydroxy-(R)-clarithromycin achieve higher concentrations in alveolar macrophages than in plasma. biomedres.us

Mean middle ear fluid concentrations of this compound in children varied from 3.0 to 8.3 µg/g, and for 14-hydroxythis compound, the range was 1.5–3.8 µg/g, reliably exceeding mean plasma concentrations. dovepress.com

Metabolism and Active Metabolites (e.g., 14-hydroxythis compound)

This compound undergoes rapid first-pass metabolism primarily in the liver, which reduces its systemic bioavailability. biomedres.usnih.govwikipedia.orgwho.int It is primarily metabolized by cytochrome P450 (CYP) 3A isozymes, particularly CYP3A4. nih.govresearchgate.net this compound is extensively metabolized into at least eight metabolites through processes including hydroxylation at the 14 position, N-demethylation, and hydrolysis of the cladinose sugar. researchgate.net

The major and microbiologically active metabolite is 14-hydroxy-(R)-clarithromycin. biomedres.usnih.govnih.govwikipedia.orgresearchgate.net This metabolite is formed by CYP3A4 and accounts for approximately 20% of the metabolites derived from the parent drug. biomedres.usresearchgate.net The formation of 14-hydroxythis compound is stereospecific, yielding the (R)-epimer as the main active form. researchgate.netresearchgate.net An inactive metabolite, 14-(S)-hydroxythis compound, is also formed. researchgate.net Another inactive metabolite is N-desmethylthis compound. wikipedia.org

The pharmacokinetics of this compound are non-linear due to the saturation of hepatic metabolism at higher doses. biomedres.uswho.int This saturation, particularly of CYP3A4-mediated metabolism, can lead to increased plasma concentrations and longer half-lives of this compound with higher doses. biomedres.uswho.intresearchgate.netthieme-connect.com this compound is also a potent inhibitor of intestinal and hepatic CYP3A4 activity, which can lead to autoinhibition of its own metabolism and affect the metabolism of coadministered drugs. researchgate.netasm.org Modeling studies have successfully described this autoinhibition. researchgate.netasm.org

Elimination Pathways and Half-Life

This compound and its metabolites are eliminated from the body through both renal and biliary excretion. nih.gov Approximately 20% to 40% of an oral dose of unchanged this compound is excreted via the kidneys, depending on the dose and formulation. biomedres.usnih.govwikipedia.orgwho.int An additional 10% to 15% of a dose is excreted in the urine as 14-hydroxythis compound. biomedres.uswikipedia.orgwho.int The remainder of the dose is excreted via the bile. nih.gov

The elimination half-life of this compound is dose-dependent and can range from 2 to 4 hours after a 250 mg dose twice daily, increasing to 5 to 7 hours after a 500 mg dose twice daily. biomedres.usnih.govwikipedia.orgwho.intresearchgate.net The 14-hydroxy metabolite has a similar or slightly longer half-life, typically ranging from 5 to 9 hours. biomedres.usnih.govwikipedia.org

In individuals with normal renal function, the half-lives of this compound and its 14-hydroxy metabolite after a 500 mg dose are approximately 5 and 7 hours, respectively. nih.gov Renal impairment significantly affects the elimination of this compound and its metabolite, leading to increased plasma concentrations and prolonged half-lives. nih.govnih.gov For instance, at a creatinine clearance of 30 to 80 mL/min, this compound's half-life is around 12 hours, increasing to 32 hours when creatinine clearance falls below 30 mL/min. nih.gov The half-life of 14-hydroxythis compound can increase to 47 hours with lower creatinine clearance. nih.gov

The terminal disposition half-life values in sputum have been reported to be 1.3- to 1.6-fold longer than those in serum for both this compound and its active metabolite. nih.gov

Effects on Specific Bacterial Populations (e.g., Enterobacteria, Bifidobacterium, Lactobacillus)

Research indicates that this compound decreases the populations of certain bacterial groups, including Enterobacteria, Bifidobacterium, and Lactobacillus species. bmj.comnih.govnih.govresearchgate.neturologyresearchandpractice.org For instance, one study observed a significant reduction in Escherichia coli (a type of Enterobacteria) during this compound treatment. bmj.comresearchgate.net Similarly, studies consistently report sustained reductions in the abundance and diversity of Bifidobacterium and Lactobacillus species following this compound administration. bmj.comnih.govnih.govresearchgate.neturologyresearchandpractice.org Conversely, some studies have noted increases in other populations, such as Enterobacter, Citrobacter, Klebsiella, and Pseudomonas, including resistant aerobic Gram-negative rods, after this compound treatment. bmj.comresearchgate.net

Here is a summary of the effects of this compound on specific bacterial populations:

Short-term vs. Long-term Microbiota Changes

The effects of this compound on the gut microbiota can vary in duration. Following the cessation of treatment, gut bacteria can recover to their baseline state within a few weeks in most individuals. bmj.comnih.govnih.gov However, some studies suggest longer-term effects, with alterations persisting from 2 to 6 months. bmj.comnih.govnih.gov In some cases, the microbiota has remained perturbed for up to four years post-treatment. plos.orgnih.gov For example, one study noted that while E. coli levels returned to normal 28 days after the end of treatment, the microflora in all subjects returned to normal after 35 days. bmj.comresearchgate.net Another study reported that bacterial abundance was not normalized 2 months after antibiotics were stopped. nih.gov

Impact on Metabolism of Co-administered Drugs

The inhibition of CYP3A4 by this compound can significantly impact the metabolism of drugs that are substrates for this enzyme. cbg-meb.nl Co-administration of this compound with drugs primarily metabolized by CYP3A4 can lead to elevated drug concentrations in the bloodstream. cbg-meb.nl This increase in systemic exposure can enhance or prolong both the therapeutic effects and the adverse effects of the co-administered drug. cbg-meb.nl this compound also inhibits P-glycoprotein (P-gp), an efflux pump that can affect the transport and elimination of various drugs, further contributing to altered drug concentrations. drugbank.comnih.govbcpharmacists.orgpharmacytimes.com

Specific Drug-Drug Interaction Mechanisms

This compound's inhibition of CYP3A4 and P-gp contributes to clinically significant interactions with several drugs:

Linezolid: While not explicitly detailed in the search results regarding a direct interaction mechanism with this compound via CYP3A4, Linezolid's metabolism can be affected by CYP enzymes, and interactions with macrolides are possible. (Insufficient specific mechanism information found in provided results).

Cyclosporin: this compound significantly increases cyclosporine blood concentrations by inhibiting its metabolism, which is primarily catalyzed by CYP3A4. nih.govnih.govjournalmc.orgdrugs.com This inhibition reduces cyclosporine clearance. nih.govnih.gov Additionally, this compound may increase gut absorption of cyclosporine by inhibiting intestinal wall metabolism and can interfere with P-gp mediated elimination. journalmc.orgdrugs.comnih.gov This interaction can lead to cyclosporine toxicity, including nephro- and neurotoxicity. nih.govnih.govdrugs.com

Carbamazepine: this compound can significantly increase serum carbamazepine levels. researchgate.netdrugs.comnih.govdrugs.com The mechanism is likely the inhibition of hepatic CYP3A4 isoenzymes, which are extensively involved in carbamazepine metabolism. researchgate.netdrugs.comnih.gov This interaction can result in transitory carbamazepine overdosage symptoms such as ataxia, dizziness, diplopia, nausea, vomiting, and drowsiness. researchgate.netnih.gov

Cisapride: Concomitant administration of this compound and cisapride is contraindicated due to the potential for severe drug interaction effects. cbg-meb.nl this compound significantly increases plasma concentrations of cisapride by inhibiting its metabolism via CYP3A4. drugs.comnih.govresearchgate.net Elevated cisapride levels are associated with QT prolongation and serious cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. cbg-meb.nldrugs.comnih.govresearchgate.net

Statins: this compound inhibits CYP3A4, OATP1B1, and OATP1B3 transporters, leading to increased blood levels of statins metabolized by these pathways. sps.nhs.ukresearchgate.netnih.gov This increases the risk of muscle disorders, such as myopathy and rhabdomyolysis. sps.nhs.ukresearchgate.netnih.govcmaj.camedsafe.govt.nz Statins extensively metabolized by CYP3A4, such as simvastatin and lovastatin, are expected to have substantially increased systemic exposure (greater than 5-fold AUC increase) when co-administered with this compound. ebmconsult.comresearchgate.netnih.gov Atorvastatin and pitavastatin levels may moderately increase (2- to 4-fold AUC increase), while pravastatin exposure may slightly increase (around 2-fold). researchgate.netnih.gov Fluvastatin and rosuvastatin are expected to have little effect. researchgate.netnih.gov

Colchicine: this compound interacts with colchicine by acting as an inhibitor of both CYP3A4 and P-glycoprotein, increasing colchicine's oral bioavailability and decreasing its hepatic metabolism and clearance. nih.govbcpharmacists.orgpharmacytimes.comdrugs.comnjmonline.nl This can lead to significantly increased serum concentrations of colchicine and potentially life-threatening adverse reactions, including myopathy, neuropathy, multiorgan failure, and pancytopenia. nih.govbcpharmacists.orgpharmacytimes.comdrugs.comnjmonline.nl

QT Interval Prolongation and Torsades de Pointes

This compound has been identified as an antimicrobial with the potential to prolong the QT interval. medscape.com The mechanism by which this compound induces QT prolongation is thought to be through the inhibition of the rapidly activating delayed rectifier potassium current (IKr) in cardiac myocytes. medscape.comnih.govrevespcardiol.orgbmj.comnih.gov This current, also known as the hERG channel current (IhERG), plays a crucial role in cardiac repolarization. medscape.comnih.govnih.gov Inhibition of IKr delays repolarization, which is manifested as an increase in the duration of the QT interval. medscape.comnih.gov Sufficient QT prolongation increases the risk of developing Torsades de Pointes (TdP), a potentially fatal polymorphic ventricular tachycardia. medscape.comuspharmacist.cominternationalscholarsjournals.comwikipedia.org Delayed repolarization can lead to early afterdepolarizations, proarrhythmic cellular events that may trigger TdP. medscape.com Exacerbated transmural heterogeneity of repolarization with IKr blockade may also contribute to a substrate for re-entrant arrhythmia. medscape.com

Coronary Vasospasms and Kounis Syndrome

This compound has been linked to coronary vasospasms, which can cause acute coronary syndrome. nih.gov Kounis syndrome, defined as angina and myocardial infarctions caused by allergic coronary vasospasms, has been suggested as a possible reason for the incidence of myocardial infarctions and increased cardiovascular mortality associated with this compound. nih.gov Hypersensitive coronary disorders triggered by various factors, including drugs, are suspected to cause Kounis syndrome. nih.gov While the exact mechanism of this compound-induced coronary vasospasm is not fully elucidated, allergic or hypersensitivity reactions may play a role. nih.gov

Accumulation of Metabolites in Central Nervous System

One proposed mechanism involves the accumulation of this compound's active metabolite, 14-hydroxythis compound, in the central nervous system (CNS). eurannallergyimm.com this compound is metabolized by the liver, primarily via the cytochrome P450 (CYP) 3A4 isoenzyme, into 14-hydroxythis compound, which also possesses antimicrobial activity. pediatriconcall.comdrugbank.comfda.gov While this compound and its metabolite distribute into body tissues, their penetration into the cerebrospinal fluid is not well-documented in humans. fda.gov However, in patients with impaired renal function, the elimination half-life of this compound and its 14-hydroxy metabolite can be prolonged, potentially leading to increased serum concentrations and, in some cases, higher CNS concentrations, which may contribute to neurotoxicity. turkjnephrol.orgnih.govrwandafda.gov.rw

Altered Neurotransmitter Levels

Another hypothesis suggests that this compound may influence neurotransmitter levels. Some research indicates that this compound might act as a gamma-aminobutyric acid (GABA)-A receptor antagonist, increasing neuronal excitability. psychiatrictimes.comjournalagent.comnih.govaasm.org This potential GABA-A antagonism could contribute to neuropsychiatric symptoms like seizures, encephalopathy, and hallucinations. psychiatrictimes.comnih.gov Additionally, increased levels of blood cortisol and prostaglandins have been associated with mania and are considered potential contributors to macrolide-induced psychiatric reactions. eurannallergyimm.com

Hoigne's Syndrome

Hoigne's syndrome, also known as antibiomania, is a rare acute neuropsychiatric disorder characterized by symptoms such as agitation, hallucinations, and delirium, typically occurring after the administration of certain antibiotics. turkjnephrol.orgjournalagent.comdergipark.org.tr While most commonly associated with procaine penicillin, Hoigne's syndrome has also been reported in rare cases following this compound treatment. turkjnephrol.orgdergipark.org.trturkjnephrol.org The mechanism underlying this compound-associated Hoigne's syndrome is unclear. turkjnephrol.org However, it has been suggested that inhibition of hepatic CYP3A4 by this compound may play a role in inducing psychiatric reactions. turkjnephrol.org Impaired kidney function, which can alter the blood-brain barrier, might also increase CNS concentrations of this compound, potentially strengthening neurotoxic effects and contributing to Hoigne's syndrome, particularly in susceptible individuals like elderly patients or those with renal insufficiency. turkjnephrol.org

HPLC-UV and HPLC-ECD for this compound and Metabolite Quantification

HPLC with UV detection can be used for this compound quantification, although its sensitivity can be limited, particularly for low concentrations in biological matrices, due to this compound's weak UV absorbance at wavelengths below 210 nm. mdpi.comwho.intrroij.com Despite this, HPLC-UV methods with pre-column derivatization have been developed and validated for this compound determination in rat plasma, showing linearity over a range of 0.1-10 µg/mL with a limit of quantification (LOQ) of 0.1 µg/mL. researchgate.netnih.gov

HPLC coupled with electrochemical detection (HPLC-ECD) is a sensitive and selective method for quantifying this compound in various matrices, including human plasma and pharmaceutical dosage forms. mdpi.comresearchgate.netbrieflands.com this compound's tertiary amino group is electrochemically active, making ECD a suitable detection technique. mdpi.comrroij.com HPLC-ECD methods have reported detection limits as low as 0.01 µg/mL and LOQs of 20 ng/mL in human plasma. mdpi.combrieflands.comnih.gov These methods have been successfully applied in pharmacokinetic and bioequivalence studies. mdpi.combrieflands.comnih.gov

Simultaneous analysis of this compound, its active metabolite 14-hydroxy-clarithromycin, and its degradation product decladinose this compound has been achieved using HPLC-ECD in rat plasma, gastric juice, and gastric tissue. nih.gov

UPLC-MS/MS for Bioanalytical Method Development

Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) offers high sensitivity, selectivity, and speed for the quantitative determination of this compound in biological matrices like human plasma. researchgate.netresearchgate.netcore.ac.uk This technique is widely used in bioanalytical method development to support pharmacokinetic and bioequivalence studies. researchgate.netresearchgate.netcore.ac.ukijper.org

UPLC-MS/MS methods for this compound quantification typically involve liquid-liquid extraction from plasma, followed by chromatographic separation on a C18 column and detection using positive ion electrospray tandem mass spectrometry in multiple reaction monitoring (MRM) or selected reaction monitoring (SRM) mode. researchgate.netresearchgate.netcore.ac.uk These methods have demonstrated high sensitivity with LOQs as low as 0.8 ng/mL and wide linear ranges. researchgate.netcore.ac.uk They are characterized by good accuracy, precision, and recovery, and are suitable for supporting clinical pharmacokinetic studies. researchgate.netresearchgate.netcore.ac.uk

Therapeutic Drug Monitoring (TDM) Methodologies

Therapeutic Drug Monitoring (TDM) of this compound is important for optimizing treatment outcomes, especially in specific patient populations or infections. ijper.org Chromatographic methods, particularly HPLC with sensitive detectors like ECD or coupled with mass spectrometry (LC-MS/MS, UPLC-MS/MS), are the primary tools for TDM of this compound in biological fluids. who.intbrieflands.comnih.govijper.org

These methodologies enable the accurate measurement of this compound concentrations in plasma or serum, allowing clinicians to adjust dosages to maintain concentrations within the therapeutic window and minimize toxicity. ijper.org The sensitivity and specificity of techniques like UPLC-MS/MS are particularly advantageous for TDM, allowing for the reliable quantification of low drug levels. core.ac.ukijper.org