Pharmacokinetic-toxicodynamic Modeling to Elucidate the Involvement of Dorsal Root Ganglion Neuron in Oxaliplatin-induced Peripheral Neuropathy.

Background/aim: Oxaliplatin (L-OHP)-induced peripheral neuropathy (OIPN) limits L-OHP dosage due to nerve cell damage in the dorsal root ganglion (DRG) caused by platinum (Pt). Despite various recommended approaches for OIPN management, no effective approach has been established. The aim of this study was to evaluate Pt distribution into DRG after repeat administrations of L-OHP in rats and to develop a pharmacokinetic-toxicodynamic (PK-TD) model using Pt concentrations in DRG to predict neuropathy severity.

Pharmacokinetic evaluation of oxaliplatin combined with S-1 (SOX) chemotherapy in a rat model of colorectal cancer with acute kidney injury: predictive renal biomarkers for dose optimisation.

Dose adjustment based on renal function is essential in S-1, which contains the 5‑fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats.

Comparing the pharmacokinetics and organ/tissue distribution of anti-methicillin-resistant agents using a rat model of sepsis.

Sepsis is a major cause of death, and sepsis-derived physiological changes complicate the understanding of drug distribution in organs/tissues, which determines the efficacy and toxicity of antimicrobial agents. In this study, we evaluated and compared the pharmacokinetics of methicillin-resistant treatment agents in sepsis with that of vancomycin, arbekacin, linezolid, and daptomycin.Rat models of sepsis were prepared using caecal ligation puncture.

Associations of Plasma Concentration Profiles of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-Transporter Type 2, with Its Effects in Japanese Patients with Type 2 Diabetes Mellitus.

This study was conducted to evaluate the long-term plasma concentration profiles of dapagliflozin and its effects on the glycated hemoglobin (HbA1c) level, body weight, and estimated glomerular filtration rate (eGFR) in 72 Japanese outpatients with type 2 diabetes mellitus (T2DM) receiving metformin and a dipeptidyl peptidase-4 inhibitor. At baseline, HbA1c level, body weight, and eGFR were 6.9 ± 0.

Safety, efficacy, and analysis of key parameters after prophylactic administration of a sustained-release formulation of azithromycin in lung cancer surgery.

Background: The current use of prophylactic antibiotics for lung cancer surgery requires modification in aging individuals with impaired lung function. A sustained-release formulation of azithromycin (AZM-SR) could help resolve some of these challenges with its sustained antibacterial and anti-inflammatory effects. The aim of this study was to examine the safety and efficacy of AZM-SR in lung cancer surgery as well as its anti-inflammatory effect.

Comparison of In Vivo Transportability of Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Agents Into Intracellular and Extracellular Tissue Spaces in Rats.

The pathogenic bacterium Staphylococcus aureus can penetrate host cells. However, intracellular S. aureus is not considered during antimicrobial agent selection in clinical chemotherapy because of the lack of information about drug transportability into cells in vivo.

Population Pharmacokinetic Model-Based Evaluation of Circadian Variations in Plasma 5-Fluorouracil Concentrations During Long-Term Infusion in Rats: A Comparison With Oral Anticancer Prodrugs.

Circadian fluctuations in the plasma concentration of 5-fluorouracil impede the accurate estimation of target therapeutic concentrations in the long-term infusion or oral 5-fluorouracil-based prodrug regimen. We evaluated the circadian patterns of plasma 5-fluorouracil concentrations in rats using population pharmacokinetic model. Rats were divided into 2 groups, and a continuous infusion (50 mg/m/h) for 48 h was initiated with or without a bolus injection of 60 mg/kg 5-fluorouracil.

Assessment of pharmacokinetic variations of capecitabine after multiple administration in rats: a physiologically based pharmacokinetic model.

Purpose: Capecitabine is a prodrug of 5-fluorouracil (5-FU) used for the treatment of colorectal cancer, with a two-week course of administration. However, the variance in plasma concentration and metabolic enzyme activities after multiple administration of capecitabine and its metabolites is unknown. The aim of this study was to identify the variance and predict the plasma concentration profile of capecitabine and its metabolites, using metabolic enzyme activities, to develop a more effective and safer medication.

Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer.

To investigate the exposure-safety relationships of afatinib in Japanese population, we performed population pharmacokinetics (PK) analysis of afatinib in Japanese advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutation. Plasma samples were collected at 0.5-1, 2-3, 8-12, and 24 h after oral afatinib (40 mg) administration on day 1 and day 8.

Establishment of the experimental procedure for prediction of conjugation capacity in mutant UGT1A1.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an enzyme that is found in the endoplasmic reticulum membrane and can reportedly have a large number of amino acid substitutions that result in the reduction of glucuronidation capacity. For example, adverse drug reactions when patients receive CPT-11 (irinotecan) such as in cancer chemotherapy are caused by amino acid substitutions in UGT1A1. We previously found that the extent of the docking when the hydroxyl residue of bilirubin was oriented toward UDP-glucuronic acid correlated with in vitro conjugation capacity.

Pharmacokinetics and lung distribution of macrolide antibiotics in sepsis model rats.

Recent studies have shown azithromycin-specific clinical efficacy against macrolide-resistant strains of , despite the low susceptibility of the bacteria . This discrepancy complicates dosing and selection for treatment of macrolide-resistant strains. Although phagocyte delivery of azithromycin to inflamed tissues is considered a possible factor for clinical efficacy, there is a lack of sufficient evidence, and other pharmacokinetic factors under systemic inflammation may contribute.

Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: A surrogate biomarker for dihydropyrimidine dehydrogenase activity.

Capecitabine is a 5-fluorouracil (5-FU) derivative that is used widely in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH ) to uracil (Ura) is expected to gain relevance as an indirect-response biomarker to estimate the activity of dihydropyrimidine dehydrogenase (DPD). The latter is a rate-limiting enzyme in the catabolism of 5-FU in the capecitabine-based regimen.

Circadian variations in the pharmacokinetics of the oral anticancer agent tegafur-uracil (UFT) and its metabolites in rats.

Uracil-tegafur (UFT) is an oral anticancer drug containing uracil and 5‑fluorouracil prodrug tegafur and is widely used for adjuvant chemotherapy of colorectal cancer. Although clinical data show circadian variations in plasma 5‑fluorouracil concentrations during its long-term infusion, and feasibility studies of chronomodulated administration have been previously reported, the circadian pattern in plasma 5‑fluorouracil concentration after UFT administrations remains unclear. The aim of this study was to identify factors causing circadian variations in UFT pharmacokinetics and estimate circadian patterns of plasma 5‑fluorouracil concentration corresponding to UFT dosing time in rats.

Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors.

In Japan, sodium-glucose co-transporter type 2 (SGLT2) inhibitors have been reported to be associated with serious skin and subcutaneous tissue disorders. A post-marketing surveillance (PMS) study suggested that the association was specific for ipragliflozin and, to a lesser extent for dapagliflozin. These studies were performed to confirm the association of 6 SGLT2 inhibitors with serious skin disorders in a clinical setting, to elucidate the role of melanin in serious skin disorders and to understand the underlying mechanisms.

Co-precipitation molecules hemopexin and transferrin may be key molecules for fibrillogenesis in TTR V30M amyloidogenesis.

The disease model of familial amyloidotic polyneuropathy-7.2-hMet30 mice-manifests amyloid deposition that consists of a human amyloidogenic mutant transthyretin (TTR) (TTR V30M). Our previous study found amyloid deposits in 14 of 27 7.

Circadian variations in the pharmacokinetics of capecitabine and its metabolites in rats.

Capecitabine, an orally available prodrug of 5-fluorouracil, is widely used to treat patients with colorectal cancer. Although various studies have shown circadian variations in plasma 5-fluorouracil concentrations during long-term infusion, it is still unknown whether circadian variations also exist following administration of capecitabine. The present study aimed to investigate whether the pharmacokinetics of capecitabine and its metabolites, including 5-fluorouracil, vary according to administration time in rats.

CSP-1103 (CHF5074) stabilizes human transthyretin in healthy human subjects.

Hereditary amyloid polyneuropathy is a type of protein misfolding disease. Transthyretin (TTR) is a homotetrameric serum protein and TTR tetramer dissociation is the limiting step in amyloid fibril formation. Thus, prevention of TTR dissociation is a promising therapeutic approach and some TTR stabilizers have been approved for the treatment of TTR amyloidosis.

Dissolving Microneedles as Skin Allergy Test Device.

The possibility of using dissolving microneedles (DMs) as a skin allergy test device was studied in rats. Poly-L-arginine was used as a model allergen. Dextran was used to prepare three kinds of DM array chips containing different doses of poly-L-arginine: 17.

A simple and rapid LC-MS/MS method for quantitation of luseogliflozin in rat plasma and its application to a PK study.

Aim: Luseogliflozin is a novel sodium-dependent glucose cotransporter-2 inhibitor for the treatment of Type 2 diabetes mellitus. To assist pharmacokinetic and toxicodynamic studies, a rapid LC-MS/MS method were developed and validated for the quantitation of luseogliflozin in rat plasma.

Results: Sample preparation was carried out using simplified protein precipitation and liquid-liquid extraction procedures, and the run time was only 4 min.

Dissolving microneedles for enhanced local delivery of capsaicin to rat skin tissue.

Capsaicin-loaded dissolving microneedles (DMNs) were prepared to investigate the analgesic effect of capsaicin on the skin. The dimensions of each microneedle (MN) were as follows: diameter of the basement, 17 mm; length, 500 μm; and width, 300 μm. The average capsaicin content in the DMNs loaded with a low and high dose of capsaicin was 8.