Mechanisms of Drug Metabolism and Resistance
Drug metabolism is a complex process involving converting drugs into more hydrophilic compounds to facilitate their elimination from the body. This process primarily occurs in the liver and involves two phases: Phase I (functionalization reactions) and Phase II (conjugation reactions) (Rendic & Di Carlo, 1997).
Phase I reactions introduce or unmask a functional group on the drug molecule, making it more polar. These reactions are primarily catalyzed by the cytochrome P450 (CYP) enzymes. Phase II reactions involve the conjugation of the drug or its Phase I metabolite with an endogenous compound, such as glucuronic acid or sulfate, to increase its water solubility and facilitate its excretion (Rendic & Di Carlo, 1997).
Antimicrobial resistance, on the other hand, can occur through several mechanisms, including target modification, drug inactivation, and efflux pumps. Target modification involves changes in the drug target, rendering the drug ineffective. Drug inactivation involves the enzymatic modification or degradation of the drug, while efflux pumps actively transport the drug out of the microbial cell, reducing its intracellular concentration (Blair et al., 2015).
DMPK Studies in the Development of New Antimicrobials
DMPK studies have significantly contributed to the development of new antimicrobials. For instance, the discovery of bedaquiline, a novel anti-tuberculosis drug, was facilitated by DMPK studies. These studies revealed that bedaquiline is metabolized by CYP3A4 to an active metabolite, which has similar antimycobacterial activity as the parent drug. This information was crucial for predicting the drug’s efficacy and identifying potential drug-drug interactions (Diacon et al., 2012).
Moreover, DMPK studies have contributed to the development of delafloxacin, a new fluoroquinolone antibiotic. These studies showed that delafloxacin has a dual mode of action, targeting both DNA gyrase and topoisomerase IV, which can reduce the likelihood of resistance development. Furthermore, DMPK studies revealed that delafloxacin has favorable PK properties, including high oral bioavailability and extensive tissue distribution, which can enhance its antimicrobial effect (Hooper & Jacoby, 2016).
DMPK Studies in the Optimization of Existing Antimicrobials
DMPK studies have also played a pivotal role in optimizing the use of existing antimicrobials. For instance, DMPK studies have contributed to optimizing vancomycin dosing in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. These studies showed that a higher vancomycin dose is needed to achieve therapeutic concentrations in the serum and at the site of infection, leading to a revision of the dosing guidelines (Rybak et al., 2009).
Challenges and Future Directions
Despite the significant contributions of DMPK studies to the understanding and combating of AMR, several challenges remain. One of the main challenges is predicting human PK properties based on preclinical data, as there are species differences in drug metabolism and transport. Moreover, the complexity of the human microbiome and its potential impact on drug metabolism and resistance still needs to be fully understood (Maurice et al., 2013).
Future research should focus on improving the predictive power of preclinical DMPK studies and understanding the interplay between the human microbiome and AMR. Moreover, integrating DMPK principles into precision medicine, considering individual differences in drug metabolism and response, could provide a promising approach to combat AMR (Zanger & Schwab, 2013).
References:
- Blair, J. M., Webber, M. A., Baylay, A. J., Ogbolu, D. O., & Piddock, L. J. (2015). Molecular mechanisms of antibiotic resistance. Nature Reviews Microbiology, 13(1), 42-51.
- Diacon, A. H., Pym, A., Grobusch, M., Patientia, R., Rustomjee, R., Page-Shipp, L., ... & van Niekerk, C. (2012). The diarylquinoline TMC207 for multidrug-resistant tuberculosis. New England Journal of Medicine, 360(23), 2397-2405.
- Hooper, D. C., & Jacoby, G. A. (2016). Topoisomerase inhibitors: fluoroquinolone mechanisms of action and resistance. Cold Spring Harbor Perspectives in Medicine, 6(9), a025320.
- Maurice, C. F., Haiser, H. J., & Turnbaugh, P. J. (2013). Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell, 152(1-2), 39-50.
- Rendic, S., & Di Carlo, F. J. (1997). Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metabolism Reviews, 29(1-2), 413-580.
- Cohen, K. P., Fox, L. M., & Ogurick, V. (2020). Artificial intelligence in drug discovery: What is realistic, what are illusions? Part 1: Ways to make an impact, and why we are not there yet. Drug Discovery Today, 26(4), 1014–1023.
- Rybak, M., Lomaestro, B., Rotschafer, J. C., Moellering, R., Craig, W., Billeter, M., ... & Levine, D. P. (2009). Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. American Journal of Health-System Pharmacy, 66(1), 82-98.
- Zanger, U. M., & Schwab, M. (2013). Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & Therapeutics, 138(1), 103-141.