Clinical validation of the suppressive impact of letrozole on liver fibrosis in patients with breast cancer undergoing continuous letrozole administration: A retrospective study.

Treatment strategies for preventing liver fibrosis have not yet been established. Letrozole, widely used for breast cancer, has recently been reported to suppress liver fibrosis in murine models. Therefore, we aimed to validate the suppressive effects of letrozole on liver fibrosis in the clinical setting.

Directional Drug Transport through Membrane-Supported Monolayers of Human Liver-Derived Cell Lines.

The aim of this work is to develop a new assay system for screening biliary excretion drugs. When monolayers of human liver-derived cell lines HepG2 and Huh-7 were grown on an insert membrane, the efflux ratio (ER: ratio of the apparent permeability coefficient in the basal-to-apical direction (P) to that in the apical to basal direction (P)) of sulfobromophthalein (BSP), a model substrate of multidrug resistance-associated protein 2 (MRP2), was greater than 1.0, indicating transport of BSP in the efflux direction.

A multilaboratory validation study of LC/MS biomarker assays for three lysophosphatidylcholines.

Although the fit-for-purpose approach has been proposed for validation procedures and acceptance criteria for biomarker assays, practical biomarker assays to facilitate clinical application and regulatory documents on biomarker assays remain limited.  We assigned six independent laboratories and selected three lysophosphatidylcholines (LPCs): LPC(16:0), LPC(18:0) and LPC(18:1) as model biomarkers. Using LC-MS, the following key validation parameters were evaluated: calibration curve, carryover, parallelism, precision and relative accuracy and these values were similar among all laboratories.

Bioanalysis of therapeutic monoclonal antibody by peptide adsorption-controlled LC-MS.

We aimed to develop an easy, low-cost and versatile mass spectrometric method for the bioanalysis of a therapeutic monoclonal antibody (mAb) in human serum that employs peptide adsorption-controlled (PAC)-LC/MS using selected reaction monitoring mode (LC-MS/MS-SRM). Rituximab was used as a model mAb. To apply the method to human serum samples, a peptide of the complementarity-determining region was selected as the surrogate peptide.

Generic MS-based method for the bioanalysis of therapeutic monoclonal antibodies in nonclinical studies.

A generic bioanalytical method was developed to quantify therapeutic IgG1 monoclonal antibodies (mAbs) in mouse sera by combining an easy sample preparation method with LC/MS using selected reaction monitoring. Rituximab and trastuzumab were used as model mAbs. A synthetic stable isotope-labeled peptide or a stable isotope-labeled mAb was used as an internal standard.

Effect of food thickener and jelly wafer on the pharmacokinetics of levofloxacin orally disintegrating tablets.

This study was designed to determine the effects of a food thickener and deglutition aid jelly for oral administration, jelly wafer, on the pharmacokinetics of levofloxacin orally disintegrating tablets. With an increase in immersion time, the disintegration time of levofloxacin orally disintegrating tablets immersed in food thickener was prolonged, whereas that of the tablets immersed in jelly wafer was shortened. The dissolution behavior of non-immersed levofloxacin orally disintegrating tablets was not similar to that of tablets immersed in food thickener, but was similar to that of tablets immersed in jelly wafer.

Uremic serum residue decreases SN-38 sensitivity through suppression of organic anion transporter polypeptide 2B1 in LS-180 colon cancer cells.

Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue.

Evaluation of miR-122 to Predict High Dose Acetaminophen-Induced Liver Injury in Mice: The Combination Uses of 5-Fluorouracil.

Administration of high doses of acetaminophen (APAP) is known to cause drug-induced liver injury (DILI) in humans. Therefore, the detection or prediction of these side-effects at an early stage using appropriate biomarkers is the need of the hour. Micro RNA (miR)-122 is expected to be a novel biomarker for liver injury.

Effects of Uremic Serum Residue on OATP1B1- and OATP1B3-Mediated Pravastatin Uptake in OATP-Expressing HEK293 Cells and Human Hepatocytes.

Patients with end-stage renal disease have increased plasma concentrations of statins, which is a risk factor for rhabdomyolysis, as well as elevated levels of uremic toxins (UTs). We investigated the effects of uremic serum residue and UTs on organic anion-transporting peptide (OATP1B1)- and OATP1B3-mediated pravastatin uptake. We evaluated the effects of normal serum residue with four UTs (hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furan propionate, indole-3-acetic acid, and 3-indoxyl sulfate) and uremic serum residue on pravastatin uptake by OATP1B1- or OATP1B3-expressing HEK293 cells.

[Effect of pH and Additives on the Compatibility between Vancomycin and Furosemide Injections].

　The physicochemical compatibility between injections of different agents is very important. An injection of the antibiotic vancomycin (VCM) is acidic and its standard pH range is 2.5-4.

Evaluation of Trace Elements in Augmentation of Statin-Induced Cytotoxicity in Uremic Serum-Exposed Human Rhabdomyosarcoma Cells.

Patients with end-stage kidney disease (ESKD) are at higher risk for rhabdomyolysis induced by statin than patients with normal kidney function. Previously, we showed that this increase in the severity of statin-induced rhabdomyolysis was partly due to uremic toxins. However, changes in the quantity of various trace elements in ESKD patients likely contribute as well.

Uremic toxins enhance statin-induced cytotoxicity in differentiated human rhabdomyosarcoma cells.

The risk of myopathy and rhabdomyolysis is considerably increased in statin users with end-stage renal failure (ESRF). Uremic toxins, which accumulate in patients with ESRF, exert cytotoxic effects that are mediated by various mechanisms. Therefore, accumulation of uremic toxins might increase statin-induced cytotoxicity.

Measurement of drug concentration in the stomach after intragastric administration of drug solution to healthy volunteers: analysis of intragastric fluid dynamics and drug absorption.

Purpose: To evaluate the time-profile of intragastric fluid volume in humans after intragastric administration of drug solution.

Methods: Eight healthy volunteers were intragastrically administered 150 mL of drug solution containing atenolol (non-absorbable marker) and salicylic acid, then, aliquots of gastric fluid (ca. 2 mL) were sampled for 2 h through the catheter.

Developing in vitro-in vivo correlation of risperidone immediate release tablet.

The present study was aimed to predict the absorption profile of a risperidone immediate release tablet (IR) and to develop the level A in vitro-in vivo correlation (IVIVC) of the drug using the gastrointestinal simulation based on the advanced compartmental absorption and transit model implemented in GastroPlus™. Plasma concentration data, physicochemical, and pharmacokinetic properties of the drug were used in building its absorption profile in the gastrointestinal tract. Since the fraction absorbed of risperidone in simulation was more than 90% with low water solubility, the drug met the criteria of class II of the Biopharmaceutics Classification System.

A perspective for biowaivers of human bioequivalence studies on the basis of the combination of the ratio of AUC to the dose and the biopharmaceutics classification system.

The ratio of AUC to the dose (AUC/dose) was previously found as a parameter that predicts a risk of bioinequivalence of oral drug products. On the basis of the combination of this parameter and the biopharmaceutics classification system (BCS), a perspective for biowaivers of human bioequivalence studies is discussed. Databases of bioequivalence studies using immediate-release solid oral dosage forms were disclosed by 6 Japanese generic pharmaceutical companies, and the number of subjects required for demonstrating bioequivalence between generic and reference products was plotted as a function of AUC/dose for each BCS category.

Analysis of risk factors in human bioequivalence study that incur bioinequivalence of oral drug products.

In the study of human bioequivalence (BE), newly developed oral products sometimes fail to prove BE with a reference product due to the high variability in pharmacokinetic (PK) parameters after oral absorption. In this study, risk factors that incur bioinequivalence in BE study were analyzed by applying the Biopharmaceutics Classification System (BCS). Forty-four generic products were selected from a database of BE studies in the past 10 years at Towa Pharmaceutical Co.