Evaluation of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an integral part of drug development and is recommended by regulatory agencies. In this study ...we compared various prediction methods and cutoff criteria based on in vitro inhibition data to assess the potential of a new molecular entity to inhibit OATP1B1 in vivo. In vitro (eg, IC50 , fu,p ) and in vivo (eg, dose, Cmax , change in area under the curve AUC) data for 11 substrates and 61 inhibitors for OATP1B1 were obtained from literature and Drugs@FDA, which include 107 clinical (in vivo) DDI studies. Substrate dependency and variability of IC50 values were noted. In addition to the ratio of unbound or total systemic concentration (Imax,u and Imax ) to IC50 , maximum unbound inhibitor concentration at the inlet to the liver (Iu,in,max ) was used for the estimation of "R value" where R = 1 + Iu,in,max /IC50 . Based on our analyses, Imax /Ki ≥ 0.1, R ≥ 1.04, or R ≥ 1.1 seem to be appropriate for reducing the false-negative (FN) predictions. However, as compared with R ≥ 1.1, Imax /Ki ≥ 0.1 and R ≥ 1.04 resulted in higher false positives (FPs) and lower true negatives (TNs). R ≥ 1.1, Imax,u /Ki ≥ 0.02, and R ≥ 1.25 alone, or combined criterion of Imax /Ki ≥ 0.1 and R ≥ 1.25, were reasonable to determine the need to perform clinical DDI studies with OATP1B1 substrates with similar positive and negative predictive values. Possible reasons of FP or FN from different decision criteria should be considered when interpreting prediction results, and the variability in IC50 determination needs to be understood and minimized.
Drug transporters can govern the absorption, distribution, metabolism, and excretion of substrate drugs and endogenous substances. Investigations to examine their potential impact to pharmacokinetic ...(PK) drug‐drug interactions (DDIs) are an integral part of the risk assessment in drug development. To evaluate a new molecular entity as a potential perpetrator of transporters, use of well characterized and/or clinically relevant probe substrates with good selectivity and sensitivity are critical for robust clinical DDI assessment that could inform DDI management strategy in the product labeling. The availability of endogenous biomarkers to monitor transporter‐mediated DDIs in early phases of clinical investigations would greatly benefit downstream clinical plans. This article reviews the state‐of‐the‐art in transporter clinical probe drugs and emerging biomarkers, including current challenges and limitations, delineates methods and workflows to identify and validate novel endogenous biomarkers to support clinical DDI evaluations, and proposes how these probe drugs or biomarkers could be used in drug development.
Atom probe tomography (APT) and transmission electron microscopy (TEM)/scanning transmission electron microscopy (STEM) have been used correlatively to explore atomic-scale local structure and ...chemistry of the exactly same area in the vicinity of growth front of a long-period stacking ordered (LPSO) phase in a ternary Mg-Al-Gd alloy. It is proved for the first time that enrichment of Gd atoms in four consecutive (0001) atomic layers precedes enrichment of Al atoms so that the formation of Al
Gd
clusters occurs only after sufficient Al atoms to form Al
Gd
clusters diffuse into the relevant portions. Lateral growth of the LPSO phase is found to occur by 'ledge' mechanism with the growth habit plane either {1Formula: see text00} or {11Formula: see text0} planes. The motion of ledges that give rise to lateral growth of the LPSO phase is considered to be controlled by diffusion of Al atoms.
Large variations in the maximum earthquake magnitude (
M
max
) have been observed among the world’s subduction zones. There is still no universal relationship between
M
max
and a given ...subduction-zone parameter, such as plate age, plate dip angle, or plate velocity, which suggests that multiple parameters control
M
max
. Here, we conduct exhaustive variable selections that are based on three evaluation criteria; leave-one-out cross-validation errors (LOOCVE), Akaike information criterion (AIC), and Bayesian information criterion (BIC) to determine the combination of subduction-zone parameters that best explains
M
max
. Multiple linear regression analyses are applied using 18 subduction-zone parameters as potential candidates for the explanatory variables of
M
max
. The minimum BIC is obtained when five variables (trench sediment thickness, existence of an accretionary prism, upper-plate crustal thickness, bending radius of the subducting oceanic plate, and trench depth) are selected as explanatory variables; each variable contributes positively to
M
max
. Minimum LOOCVE and AIC values are obtained when eight variables (the five parameters for BIC, plus the along-strike plate convergence rate, age of the subducting plate, and maximum depth of the subducting plate) are selected. Our selection of the trench sediment thickness and plate bending radius contributing to
M
max
is consistent with previous studies. The results show that increasing upper-plate crustal thickness results in a large
M
max
. In addition to smoothing the subducting-plate interface via subducted sediments, along-dip extension of the crustal area along the convergent plate boundary would be important for generating a large earthquake.
Graphic Abstract
The 2021 eruption of Fukutoku-Oka-no-Ba (FOB), which is a submarine volcano located at the southern end of the Izu-Ogasawara arc, produced a large number of pumice clasts that drifted to many places ...in the islands of Japan and eastern Asia. Amongst the typical gray pumice clasts, several peculiar clasts have been discovered, such as those with a black coloration and containing mafic enclaves. This study found a mostly bimineralic enclave consisting of plagioclase phenocrysts and an alkali feldspar matrix, with minor cristobalite, TiO2 minerals (anatase and rutile), and Fe sulfide. The chemical composition of the plagioclase phenocrysts is similar to that reported from the FOB pumice, and the tie line of the alkali feldspar and plagioclase in a Ca-Na-K ternary diagram indicates that they originated from melt extracted from the crystal mush of the FOB magma reservoir. The cristobalite occurs in the voids in the matrix, in which surrounding alkali feldspar compositions changed gradually along the ternary feldspar solvus of ∼ 850 °C. The formation of a cristobalite-bearing bimineralic enclave can be explained by (1) the melt was extracted and accumulated at the shallow part of the magma reservoir, which crystallized as syenitic rocks; (2) subsequent degassing-related alteration within the volcanic conduit that caused plagioclase breakdown and cristobalite crystallization; and (3) entrainment of the syenitic rock fragment by the nanolite-bearing magma being erupted from the conduit.
Isocon analysis has been widely applied to various geoscientific problems as a simple standard tool for quantitative estimation of material transfer. Despite its usefulness, similar to all material ...transfer calculations, this method generally requires the presumptive specification of immobile elements or the assumption of conservation of mass or volume. However, the validity of such assumptions is particularly controversial. Here we propose a novel data-driven method that automatically estimates the mass gain or loss of elements based on compositional data of multiple samples that have been altered from the original rock without assuming immobile elements. The proposed method uses a mathematical framework, called sparse modeling, that can extract essential information from high-dimensional datasets based on the sparsity of the system. In this case, it is assumed that some elements show higher immobility than others (i.e., the material transfer of such elements is near zero). By optimizing the evaluation function, the immobile elements are automatically selected. By inputting only the bulk compositional datasets, the user can obtain the material gain or loss with total mass change ratio for each sample relative to the reference (original) rock. The effectiveness of the method is validated and discussed using synthetic and natural sample data. Software packages are available from the authors in MATLAB function and Excel workbook forms.
To understand rheological weakening in the lower continental crust, we studied mylonites in the Paleoproterozoic Eidsfjord anorthosite, northern Norway. The zones of anorthositic mylonites range from ...a few millimeters to several meters thick, and include ultramylonites and protomylonites. They contain syn-kinematic metamorphic minerals, including Cl-bearing amphibole and scapolite. Thermodynamic analysis reveals that syn-deformational hydration reactions occurred at ∼600 °C and ∼700 MPa under CO2-bearing conditions. The protomylonites contain many fragmented plagioclase porphyroclasts. The fractures in porphyroclasts are filled with fine-grained plagioclase, suggesting that fracturing is a common mechanism of grain size reduction. The anorthite contents of fine-grained polygonal matrix plagioclase are different from those of porphyroclastic plagioclase, suggesting that the matrix grains nucleated and grew during syn-kinematic metamorphism. Plagioclase aggregates in the matrices of mylonites do not exhibit a distinct crystallographic preferred orientation, which implies that the dominant deformation mechanism was grain-size-sensitive creep. Consequently, in the lower crustal anorthositic mylonites, grain size reduction occurred via fracturing, rather than through dynamic recrystallization, leading to grain-size-sensitive creep. The syn-kinematic recrystallization of minor phases at plagioclase grain boundaries may suppress the growth of plagioclase and contribute to the development of grain-size-sensitive creep.
•Fracturing is a common mechanism of grain size reduction in anorthositic mylonites.•Syn-kinematic reactions occur under CO2-bearing, epidote-amphibolite facies conditions.•Grain-size-sensitive creep is the dominant deformation mechanism.•Syn-kinematic recrystallization of minor phases maintains grain-size-sensitive creep.
Mechanistic understanding of complex clinical drug–drug interactions (DDIs) with potential involvement of multiple elimination pathways has been challenging, especially given the general lack of ...specific probe substrates for transporters. Here, we conducted a clinical DDI study to evaluate the interaction potential of fenebrutinib using midazolam (MDZ; CYP3A), simvastatin (CYP3A and OATP1B), and rosuvastatin (BCRP and OATP1B) as probe substrates. Fenebrutinib (200 mg) increased the area under the curve (AUC) of these probe substrates twofold to threefold. To evaluate the mechanism of the observed DDIs, we measured the concentration of coproporphyrin I (CP‐I) and coproporphyrin III (CP‐III), endogenous biomarkers of OATP1B. There was no change in CP‐I or CP‐III levels with fenebrutinib, suggesting that the observed DDIs were caused by inhibition of CYP3A and BCRP rather than OATP1B, likely due to increased bioavailability. This is the first published account using an endogenous transporter biomarker to understand the mechanism of complex DDIs involving multiple elimination pathways.
Our recent studies have shown that chronic kidney disease (CKD) affects the pharmacokinetics (PKs) of cytochrome P450 (CYP)2D6‐metabolized drugs, whereas effects were less evident on CYP3A4/5. ...Therefore, the effect of CKD on the disposition of CYP1A2‐metabolized, CYP2C8‐metabolized, CYP2C9‐metabolized, CYP2C19‐metabolized, and organic anion‐transporting polypeptide (OATP)‐transported drugs was investigated. We identified dedicated CKD studies with 6, 5, 6, 4, and 12 “model” substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP, respectively. Our analyses suggest that clearance of OATP substrates decreases as kidney function declines. Similar trends were seen for CYP2C8; but overlap between some CYP2C8 and OATP substrates highlights that their interplay needs further investigation. In contrast, the effect of CKD on CYP1A2, CYP2C9, and CYP2C19 was variable and modest compared to CYP2C8 and OATP. This improved understanding of elimination‐pathway‐dependency in CKD is important to inform the need and conduct of PK studies in these patients for nonrenally eliminated drugs.
► The plasma membrane exhibits the three-tiered meso-scale domain architecture. ► The first tier is actin membrane-skeleton-induced compartments (partitioning). ► The second tier consists of raft ...domains with enormously varied sizes and lifetimes. ► The third tier is made of dynamic protein complex domains. ► Raft domains co-exist and work cooperatively with the domains of other tiers.
Virtually all biological membranes on earth share the basic structure of a two-dimensional liquid. Such universality and peculiarity are comparable to those of the double helical structure of DNA, strongly suggesting the possibility that the fundamental mechanisms for the various functions of the plasma membrane could essentially be understood by a set of simple organizing principles, developed during the course of evolution. As an initial effort toward the development of such understanding, in this review, we present the concept of the cooperative action of the hierarchical three-tiered meso-scale (2–300nm) domains in the plasma membrane: (1) actin membrane-skeleton-induced compartments (40–300nm), (2) raft domains (2–20nm), and (3) dynamic protein complex domains (3–10nm). Special attention is paid to the concept of meso-scale domains, where both thermal fluctuations and weak cooperativity play critical roles, and the coupling of the raft domains to the membrane-skeleton-induced compartments as well as dynamic protein complexes. The three-tiered meso-domain architecture of the plasma membrane provides an excellent perspective for understanding the membrane mechanisms of signal transduction.
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