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This article elucidates the metabolic pathways of rapamycin and its derivatives, intending to propose a strategy for implementing personalized medicine.

Rapamycin (sirolimus) and its derivatives are immunosuppressants and chemotherapeutic agents used in cancer treatment. As the paradigm shifts towards personalized medicine, it is essential to identify the factors impacting the effectiveness of these drugs. A study in the Journal of Personalized Medicine reviewed the metabolism of rapamycin and its derivatives and the genetic characteristics that predict their efficacy.

First Level of Analysis: Tumor Mutations and Mechanism of Action

Mechanistic target of rapamycin kinase (mTOR) is a protein kinase that forms mTORC1 and mTORC2 complexes in the cell and is involved in cell growth, nutrient metabolism, and protein synthesis. mTOR pathway activation promotes tumor growth under anaerobic and low-nutrient conditions and is facilitated by mutations in AKT, PTEN, TSC1, and TSC2 genes. Tumors with these mutations are indicators for and sensitive to rapamycin and rapalogues, which inhibit this pathway.
Rapamycin and its analogs have a lipophilic macrocyclic lactone core.

Variations in the analogs result from side-chain substitutions, which affect their solubility, bioavailability, and metabolism. These drugs bind to and inhibit the mTORC1 complex, interfering with cancer cell growth, division, metabolism, and angiogenesis. The mTORC2 complex is not directly affected but may be partially inhibited with chronic exposure, which is why rapalogues may not be fully effective alone.

Second Level: Rapalogue Metabolism     

Sirolimus and its analogs are mainly metabolized in the liver by cytochrome enzymes, particularly CYP3A4, CYP3A5, and CYP2C8, with the primary transporter being ABCB1. Side chains influence the metabolism of rapalogues with differences in cellular transport and pro-drug conversion to the active form; however, the exact mechanisms are not fully understood. Genetic variations in these enzymes can affect the drug’s efficacy and toxicity, emphasizing the need for personalized treatment with pharmacogenomic analysis of the patient, monitoring blood concentrations, and reviewing possible interference by co-administered drugs.

Third Level: Metabolism by Tumor Cells

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The effectiveness of chemotherapy relies on achieving an optimal concentration of the active drug within the tumor cells. Factors such as drug absorption, distribution, protein binding, metabolism, and transport through cancer cells affect this process. Drug metabolism occurs mainly in the liver but also in other tissues. Certain tumors can express the CYP3A4, CYP3A5, and CYP2C8 enzymes, which metabolize the rapalogues, reducing their effectiveness.

Moreover, ABCB1 is highly expressed in some tumors and can impact the transport of rapalogues out of tumor cells. Therefore, gene expression analysis of the tumor before treatment selection is suggested to improve efficacy. Since the same enzymes affect all rapamycin analogs, resistance to one may indicate resistance to others, necessitating the use of additional medications. Numerous alternative drugs targeting the mTOR pathway are under development.

Source

Delgado, A., & Enkemann, S. (2023). Three Layers of Personalized Medicine in the Use of Sirolimus and Its Derivatives for the Treatment of Cancer. Journal of Personalized Medicine, 13(5), 745. https://doi.org/10.3390/jpm13050745