Doxorubicin (DOX), a widely used drug in cancer chemotherapy, induces cell death via multiple intracellular interactions, generating reactive oxygen species and DNA-adducted configurations that induce apoptosis, topoisomerase II inhibition, and histone eviction. Despite its wide therapeutic efficacy in solid tumors, DOX often induces drug resistance and cardiotoxicity. It shows limited intestinal absorption because of low paracellular permeability and P-glycoprotein (P-gp)-mediated efflux. We reviewed various parenteral DOX formulations, such as liposomes, polymeric micelles, polymeric nanoparticles, and polymer-drug conjugates, under clinical use or trials to increase its therapeutic efficacy. To improve the bioavailability of DOX in intravenous and oral cancer treatment, studies have proposed a pH- or redox-sensitive and receptor-targeted system for overcoming DOX resistance and increasing therapeutic efficacy without causing DOX-induced toxicity. Multifunctional formulations of DOX with mucoadhesiveness and increased intestinal permeability through tight-junction modulation and P-gp inhibition have also been used as orally bioavailable DOX in the preclinical stage. The increasing trends of developing oral formulations from intravenous formulations, the application of mucoadhesive technology, permeation-enhancing technology, and pharmacokinetic modulation with functional excipients might facilitate the further development of oral DOX.

Abnormal productions of amyloid beta (Aβ) plaque and chronic neuroinflammation are commonly observed in the brain of patients with Alzheimer’s disease, and both of which induce neuronal cell death, loss of memory, and cognitive dysfunction. However, many of the drugs targeting the production of Aβ peptides have been unsuccessful in treating Alzheimer’s disease. In this study, we identified synthetic novel peroxisome proliferator-activating receptor (PPAR) agonist, DTMB, which can ameliorate the chronic inflammation and Aβ pathological progression of Alzheimer’s disease. We discovered that DTMB attenuated the proinflammatory cytokine production of microglia by reducing the protein level of NF-κB. DTMB also improved the learning and memory defects and reduced the amount of Aβ plaque in the brain of 5xFAD mice. This reduction in Aβ pathology was attributed to the changes in gliosis and chronic inflammation level. Additionally, bulk RNA-sequencing showed that genes related to inflammation and cognitive function were changed in the hippocampus and cortex of DTMB-treated mice. Our findings demonstrate that DTMB has the potential to be a novel therapeutic agent for Alzheimer’s disease. Graphical abstract

Zastaprazan (JP-1366), a novel potassium-competitive acid blocker, is a new drug for the treatment of erosive esophagitis. JP-1366 is highly metabolized in human, mouse, and dog hepatocytes but moderately metabolized in rat and monkey hepatocytes when estimated from the metabolic stability of this compound in hepatocyte suspension and when 18 phase I metabolites and 5 phase II metabolites [i.e., N-dearylation (M6), hydroxylation (M1, M19, M21), dihydroxylation (M7, M8, M14, M22), trihydroxylation (M13, M18), hydroxylation and reduction (M20), dihydroxylation and reduction (M9, M16), hydrolysis (M23), hydroxylation and glucuronidation (M11, M15), hydroxylation and sulfation (M17), dihydroxylation and sulfation (M10, M12), N-dearylation and hydroxylation (M3, M4), N-dearylation and dihydroxylation (M5), and N-dearylation and trihydroxylation (M2)] were identified from JP-1366 incubation with the hepatocytes from humans, mice, rats, dogs, and monkeys. Based on the cytochrome P450 (CYP) screening test and immune-inhibition analysis with CYP antibodies, CYP3A4 and CYP3A5 played major roles in the metabolism of JP-1366 to M1, M3, M4, M6, M8, M9, M13, M14, M16, M18, M19, M21, and M22. CYP1A2, 2C8, 2C9, 2C19, and 2D6 played minor roles in the metabolism of JP-1366. UDP-glucuronosyltransferase (UGT) 2B7 and UGT2B17 were responsible for the glucuronidation of M1 to M15. However, JP-1366 and active metabolite M1 were not substrates for drug transporters such as organic cation transporter (OCT) 1/2, organic anion transporter (OAT) 1/3, organic anion transporting polypeptide (OATP)1B1/1B3, multidrug and toxic compound extrusion (MATE)1/2K, P-glycoprotein (P-gp), and breast cancer-resistant protein (BCRP). Only M1 showed substrate specificity for P-gp. The findings indicated that drug-metabolizing enzymes, particularly CYP3A4/3A5, may have a significant role in determining the pharmacokinetics of zastaprazan while drug transporters may only have a small impact on the absorption, distribution, and excretion of this compound.

Background/Objectives: Paclitaxel (PTX) faces clinical limitations in melanoma treatment due to poor solubility, P-glycoprotein (P-gp)-mediated efflux, and systemic toxicity. This study aimed to develop PTX-loaded mesoporous silica nanoparticles (PS), which would be co-administered with curcumin (CUR) and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) to enhance intracellular accumulation and improve anti-tumor activity. CUR and TPGS were integrated with PS to inhibit P-gp-mediated PTX-efflux, to enhance the intracellular accumulation of PTX, and to improve anti-tumor activity in B16F10 cells. Methods: The physicochemical properties of PS were analyzed using standard characterization methods. The antitumor activity of PS co-administered with CUR and TPGS was evaluated using two-dimensional (2D) culture and three-dimensional (3D) spheroid assays, and also assessed in B16F10 tumor-bearing mice. The therapeutic mechanism of the PS combination was compared using apoptosis and microtubule disruption through flow cytometry and confocal microscopy. The pharmacokinetics and biodistribution of the PS combination were compared in B16F10 tumor-bearing mice. Results: PS formulations exhibited amorphous transformation with an approximate particle size of 200 nm. PS co-administered with CUR and TPGS reduced the IC₅₀ to 178.7 nM compared with 283.3 nM for free PTX in B16F10 melanoma cells and achieved significant tumor growth inhibition in B16F10 melanoma spheroid culture. The intracellular accumulation of PTX correlated with its therapeutic efficacy. Flow cytometry revealed a significant induction of both early and late apoptosis in cells treated with the PS + CUR + TPGS combination, while confocal imaging confirmed enhanced microtubule disruption. In B16F10 tumor-bearing mice, PS co-administered with CUR and TPGS demonstrated higher and selective distribution of PTX into tumor tissue without affecting systemic exposure of PTX in B16F10-xenografted mice. Conclusions: PS + CUR + TPGS combination enhanced PTX delivery by improving solubility and enhancing distribution to tumor tissue through P-gp inhibition, thereby increasing its therapeutic potential. The combination of CUR and TPGS offers synergistic apoptosis induction and microtubule disruption. Thus, the PS + CUR + TPGS combination represents a promising approach for treating drug-resistant melanomas.

Fimasartan, amlodipine, and hydrochlorothiazide are commonly used in combination therapies as antihypertensive drugs. This study aimed to develop and validate an analytical method for fimasartan, its active and major metabolite fimasartan-amide, amlodipine, and hydrochlorothiazide in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The standard calibration curves for fimasartan (1–500 ng/mL), its active and major metabolite fimasartan-amide (0.3–100 ng/mL), amlodipine (0.5–200 ng/mL), and hydrochlorothiazide (5–5000 ng/mL) were linear with R² > 0.9964, and the inter- and intra-day accuracy and precision and stability were within the acceptable criteria. Using this validated analytical method, the pharmacokinetic interaction of these triple combination drugs between single administration and concomitant administration of the triple combination was investigated; the results did not reveal a significant difference in any of the pharmacokinetic parameters. Based on these results, we investigated the effects of red ginseng extract (RGE) on the pharmacokinetics of fimasartan, fimasartan-amide, amlodipine, and hydrochlorothiazide after oral administration of the combination in rats. No significant difference was observed in the pharmacokinetic parameters of fimasartan, fimasartan-amide, amlodipine, and hydrochlorothiazide, except for the T_max values of amlodipine. The delayed T_max value of amlodipine was attributed to its decreased intestinal permeability after repeated RGE treatments. In conclusion, using a combination of antihypertensive drugs and simultaneous analytical methods, we established efficient drug interaction and toxicokinetic studies using a small number of animals.