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The aims of this study were to develop a population pharmacokinetic (PPK) model for pravastatin pharmacokinetics with regard to enterohepatic circulation (EHC) and to evaluate effects of polymorphisms in SLCO1B1 and ABCC2 on the pharmacokinetic (PK) profile of pravastatin quantitatively. A total of 636 blood samples from 57 healthy male volunteers were used. The PPK analysis was carried out using nonlinear mixed effect modeling (NONMEM) and validated by a bootstrap analysis. The PK profile of pravastatin was best described by a model of EHC with Erlang's distribution. A covariate analysis revealed that SLCO1B1*15 significantly influenced relative bioavailability (Frel); Frel was increased 1.50- and 1.95-fold in participants heterozygous and homozygous, respectively, for the *15 allele in comparison with participants without the allele. No ABCC2 polymorphism was identified as a potential covariate for pravastatin. The bootstrap analysis indicated that the PK profile of pravastatin was adequately described by the proposed PPK model. SLCO1B1*15 has a significant effect on Frel, indicating that OATP1B1 is one of the determinants of systemic exposure to pravastatin. [ABSTRACT FROM AUTHOR]

This study is aimed at developing an anisotropic elastoplastic constitutive model for geomaterials at finite strain and its stress calculation algorithm based on the fully implicit return‐mapping scheme. The Cam‐clay plasticity model is adopted as a specific prototype model of geomaterials. As a pertinent representation of deformation‐induced anisotropy in geomaterials, nonlinear rotational hardening is incorporated into the model in a theoretically reasonable manner by introducing the dual multiplicative decompositions of the deformation gradient tensor. In addition to the usual decomposition into elastic and plastic parts, the plastic part is decomposed further into a part contributing to the rotational hardening and a remainder part. The former part leads to a back stress ratio tensor related to the rotational hardening via a hyperelastic‐type hardening rule. The constitutive theory is thereby formulated on proper intermediate configurations entirely in terms of deformation‐like tensorial variables possessing invariance property, without resort to any objective rates of stress or stress‐like variables. Combining the Cam‐clay plasticity with the concept of subloading surface, a class of unconventional plasticity, enables the model to be capable of reproducing complex hardening/softening accompanied by volumetric contractive/dilative responses. Basic characteristics and predictive capability of the proposed model, as well as the accuracy of the developed numerical scheme, are verified through several numerical examples including monotonic and cyclic loadings. [ABSTRACT FROM AUTHOR]

A novel partitioning collection device comprising a glass cartridge packed with poly(dimethylsiloxane)-coated macroporous silica particles was developed for the precise quantification of polycyclic aromatic hydrocarbons in air. The analyte collection and elution performances achieved using different amounts of poly(dimethylsiloxane) coating were quantitatively evaluated. The sample retention power increased with increasing the coating, and more than 250 L of air could be collected without analyte breakthrough at a sampling temperature of 35°C. During the air collection, the moisture in the air was not retained on the particles due to the hydrophobic surface of the sorbent. A complete and rapid elution of the collected analytes from the device was accomplished by the passage of only 10 mL of acetone with ultrasonication for 1 min. The proposed method was successfully applied for the determination of airborne polycyclic aromatic hydrocarbons in tunnel air. [ABSTRACT FROM AUTHOR]

A novel sampling device based on the partition of target analytes to the extraction medium was developed for the determination of sesquiterpenes in air samples. The extraction medium was prepared by the chemical derivatization of a specially prepared macroporous silica, with a specific surface area of 2.0 m2/g. Taking advantage of the sample extraction, which was mainly based on the partition of sesquiterpenes between air and a C18-bonded phase, the extracted analytes were rapidly and quantitatively desorbed just by passing a small amount of desorption solvent for subsequent analysis by gas chromatography with mass spectrometry. Several experimental conditions, such as the sampling volume and temperature, were systematically evaluated. Under optimized conditions, desorption of the extracted analytes was completed within 1 min with a desorption efficiency of more than 99.9%, achieved using 5 mL of acetone for all the evaluated sesquiterpenes. The applicability of the developed device was confirmed by the determination of several sesquiterpenes from coniferous trees. Although further improvements of the device are required for collecting large volumes or high-temperature air samples, the potential of the developed sampling device was confirmed by determining traces of semivolatile organic compounds in air samples. [ABSTRACT FROM AUTHOR]

The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC0-24 of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems. [ABSTRACT FROM PUBLISHER]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cranberry juice has a significant inhibitory effect on CYP2C9 activity in vitro, whereas it shows a minimal effect on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate in vivo. • Information regarding the interaction between cranberry juice and other medications metabolized by CYP2C9 is limited. WHAT THIS STUDY ADDS • Cranberry juice suppressed the metabolism of diclofenac, another CYP2C9 substrate, by human liver microsomes. • Pharmacokinetic parameters of diclofenac were not altered by cranberry juice consumption in human subjects. AIM To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations. [ABSTRACT FROM AUTHOR]