ABSTRACT
Regulated cell death (RCD) pathways, such as pyroptosis, apoptosis, and necroptosis, are essential for maintaining the body's balance, defending against pathogens, and eliminating abnormal cells that could lead to diseases like cancer. Although these pathways operate through distinct mechanisms, recent genetic and pharmacological studies have shown that they can interact and influence each other. The concept of "PANoptosis" has emerged, highlighting the interplay between pyroptosis, apoptosis, and necroptosis, especially during cellular responses to infections. This article provides a concise overview of PANoptosis and its molecular mechanisms, exploring its implications in various diseases. The review focuses on the extensive interactions among different RCD pathways, emphasizing the role of PANoptosis in infections, cytokine storms, inflammatory diseases, and cancer. Understanding PANoptosis is crucial for developing novel treatments for conditions involving infections, sterile inflammations, and cancer.
ABSTRACT
Methotrexate (MTX) is an antifolate agent widely used for treating conditions such as rheumatoid arthritis and hematologic cancer. This study aimed to quantitatively interpret the drug-drug interactions (DDIs) of MTX mediated by drug transporters using physiologically-based pharmacokinetic (PBPK) modeling. An open-label, randomized, 4-treatment, 6-sequence, 4-period crossover study was conducted to investigate the effects of rifampicin (RFP), an inhibitor of organic anionic transporting peptides (OATP) 1B1/3, and febuxostat (FBX), an inhibitor of breast cancer resistance protein (BCRP), on the pharmacokinetics of MTX in healthy volunteers. PBPK models of MTX, RFP, and FBX were developed based on in vitro and in vivo data, and the performance of the simulation results for final PBPK models was validated in a clinical study. In the clinical study, when MTX was co-administered with RFP or FBX, systemic exposure of MTX increased by 33% and 17%, respectively, compared with that when MTX was administered alone. When MTX was co-administered with RFP and FBX, systemic exposure increased by 52% compared with that when MTX was administered alone. The final PBPK model showed a good prediction performance for the observed clinical data. The PBPK model of MTX was well developed in this study and can be used as a potential mechanistic model to predict and evaluate drug transporter-mediated DDIs of MTX with other drugs.
ABSTRACT
Coproporphyrin (CP)-I and CP-III are the markers of organic anion-transporting polypeptides' (OATPs) activities, and they are porphyrin metabolites that originate from heme synthesis. Furthermore, CP-I and CP-III, which are OATP1B endogenous metabolites, have gradually attracted the attention of scientists and researchers in recent years. Previous studies have also observed CP-I and CP-III levels as clinical biomarkers for predicting OATP1B inhibition in drug-drug interaction studies. To establish an accurate ultra-high performance liquid chromatography-mass spectrometry method for the quantitation of CP-I and CP-III, we reviewed previous methodological publications and applied them to a clinical pharmacology study using a human urine matrix. We used 13.25 M formic acid as a working solution for internal standards (CP-I 15N4 and CP-III d8) to avoid isobaric interference. The calibration curve showed good linearity in the range of 1-100 ng/mL, with a correlation coefficient (R2) higher than 0.996 in each validation batch. Both the between-run and within-run assays achieved good precision and accuracy, and we found that both CP-I and CP-III were stable in the pre-study validation. The method exhibited suitable dilution integrity, allowing for the re-analysis of samples with concentrations exceeding the upper limit of quantification through dilution. Overall, the application of the described method in a clinical study revealed that it can be utilized effectively to monitor drug-drug interactions mediated by OATP1B.
