Preclinical pharmacokinetics-related pharmacological effects of orally administered polysaccharides from traditional Chinese medicines: A review.

Polysaccharides (TCMPs) derived from traditional Chinese medicines (TCMs), such as Ganoderma lucidum, Astragalus membranaceus, Lycium barbarum, and Panax ginseng, are considered to be the main active constituents in TCMs. However, the significant pharmacological effects of orally administered TCMPs do not align well with their poor pharmacokinetics. This article aims to review the literature published mainly from 2010 to 2022, focusing on the relationship between pharmacokinetics and pharmacological effects. It has been found that unabsorbed TCMPs can exert local pharmacological effects in the gut, including anti-inflammation, anti-oxidation, regulation of intestinal flora, modulation of intestinal immunity, and maintenance of intestinal barrier integrity. Unabsorbed TCMPs can also produce systemic pharmacological effects, such as anti-tumor activity and immune system modulation, by regulating intestinal flora and immunity. Conversely, some TCMPs can be absorbed and distributed to various tissues, especially the liver, where they exhibit tissue-protecting effects against inflammation and oxidative stress-induced damage and improve glucose and lipid metabolism. In future studies, it is important to improve quality control and experimental design. Furthermore, research on enhancing the oral bioavailability of TCMPs, exploring the activity of TCMP metabolites, investigating pharmacokinetic interactions between TCMPs and oral drugs, and developing oral drug delivery systems using TCMPs holds great significance.

Vitamins E and A increase the passing of the P-gp substrate ivermectin into the brain in mice.

This study aimed to determine the effect of administration of oral vitamins A and E at different doses on plasma and brain concentrations of ivermectin in mice. The study was carried out on 174 Swiss Albino male mice aged 8-10 weeks. After leaving six mice for method validation, the remaining mice were randomly divided into seven groups with equal numbers of animals. Mice received ivermectin (0.2 mg/kg, subcutaneous) alone and in combination with low (vitamin A: 4000 IU/kg; vitamin E: 35 mg/kg) and high (vitamin A: 30 000 IU/kg; vitamin E: 500 mg/kg) oral doses of vitamins A and E. The plasma and brain concentrations of ivermectin were measured using high-performance liquid chromatography-fluorescence detector. We determined that high doses of vitamins A and E and their combinations increased the passing ratio of ivermectin into the brain significantly. The high-dose vitamin E and the combination of high-concentration vitamins E and A significantly increased the plasma concentration of ivermectin (P < 0.05). The high-dose vitamins E and A and their high-dose combination increased the brain concentration of ivermectin by 3, 2, and 2.7 times, respectively. This research is the first in vivo study to determine the interaction between P-gp substrates and vitamins E and A.

Cathine and cathinone disposition kinetics and neurotransmitter profile in several organs of rats exposed to a single dose of Catha edulis (Vahl) Forssk. ex Endl. extract.

OBJECTIVES: Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats. METHODS: Twenty-four adult male Wistar albino rats (250-300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method. RESULTS: The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner. CONCLUSIONS: Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest Cmax in the lung and Tmax in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone's effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations.

A comprehensive perspective on the disposition, metabolism, and pharmacokinetics of representative multi-components of Dengzhan Shengmai in rats with chronic cerebral hypoperfusion after oral administration.

ETHNOPHARMACOLOGICAL RELEVANCE: Dengzhan Shengmai capsule (DZSM), an evidence-based Chinese medicine comprising Erigeron breviscapus (Vaniot) Hand. -Mazz., Panax ginseng C.A.Mey., Ophiopogon japonicus (Thunb.) Ker Gawl., and Schisandra chinensis (Turcz.) Baill., exhibits an excellent efficacy in treating cardio- and cerebrovascular diseases. It contains caffeoyl compounds, flavonoids, saponins, and lignans as primary active components. However, so far, the characteristics of disposition, metabolism, and pharmacokinetics of its active components remain mostly unclear. AIM OF STUDY: To elucidate disposition, metabolism, and pharmacokinetics of representative components of DZSM in rats with chronic cerebral hypoperfusion (CCH) by integrating ex vivo and in situ approaches. MATERIALS AND METHODS: Exposure and distribution of absorbed prototypes and their metabolites were comprehensively investigated using sensitive LC-MS/MS and high-resolution LC-Q-TOF/MS. Pharmacokinetics of representative 16 components (12 prototypes and 4 metabolites) with different chemical categories, relatively high in vivo levels, wide tissue distribution, and reported neuroprotective activities were profiled. The ex vivo everted gut sac and in situ linked-rat models were adopted. RESULTS: Representative 12 prototypes including 6 caffeoyl compounds (CA, 5-CQA, 3-CQA, 4-CQA, 1,3-CQA, and 3,4-CQA), 1 flavonoid (Scu), 2 saponins (Rd and Rg2), and 3 lignans (SchA, SchB, and SolA) presented characteristic absorption, disposition, and pharmacokinetics profiles in CCH rats. The caffeoyl compounds and flavonoid were well absorbed, exhibited wide distribution, and underwent extensive intestinal metabolism, such as methylation, isomerization, and sulfoconjugation. For CA, 5-CQA, Scu, and 4 related metabolites, the enterohepatic circulation was observed and resulted in bimodal or multimodal pharmacokinetic profiles. Saponins showed relatively low systemic exposure and limited distribution. The PPD-type ginsenoside Rd exhibited longer elimination half-life and systemic circulation than the PPT-type ginsenoside Rg2. No enterohepatic circulation was observed regarding saponins, suggesting that the multimodal pharmacokinetic profile of Rd could be due to its multi-site intestinal absorption. Lignans presented a low in vivo exposure and broad distribution. They were mainly transformed into hydroxylated metabolites. Corresponding to its bimodal pharmacokinetic profile, one metabolite of lignans completed the enterohepatic cycle. CONCLUSION: The disposition, metabolism, and pharmacokinetic profiles of representative active components of DZSM were comprehensively characterized and elucidated.

Plasma Pharmacokinetics and Tissue Distribution of Doxorubicin in Rats following Treatment with Astragali Radix.

Doxorubicin (DOX) is an essential component in chemotherapy, and Astragali Radix (AR) is a widely used tonic herbal medicine. The combination of DOX and AR offers widespread, well-documented advantages in treating cancer, e.g., reducing the risk of adverse effects. This study mainly aims to uncover the impact of AR on DOX disposition in vivo. Rats received a single intravenous dose of 5 mg/kg DOX following a single-dose co-treatment or multiple-dose pre-treatment of AR (10 g/kg × 1 or × 10). The concentrations of DOX in rat plasma and six tissues, including heart, liver, lung, kidney, spleen, and skeletal muscle, were determined by a fully validated LC-MS/MS method. A network-based approach was further employed to quantify the relationships between enzymes that metabolize and transport DOX and the targets of nine representative AR components in the human protein−protein interactome. We found that short-term (≤10 d) AR administration was ineffective in changing the plasma pharmacokinetics of DOX in terms of the area under the concentration−time curve (AUC, 1303.35 ± 271.74 µg/L*h versus 1208.74 ± 145.35 µg/L*h, p > 0.46), peak concentrations (Cmax, 1351.21 ± 364.86 µg/L versus 1411.01 ± 368.38 µg/L, p > 0.78), and half-life (t1/2, 31.79 ± 5.12 h versus 32.05 ± 6.95 h, p > 0.94), etc. Compared to the isotype control group, DOX concentrations in six tissues slightly decreased under AR pre-administration but only showed statistical significance (p < 0.05) in the liver. Using network analysis, we showed that five of the nine representative AR components were not localized to the vicinity of the DOX disposition-associated module. These findings suggest that AR may mitigate DOX-induced toxicity by affecting drug targets rather than drug disposition.

Improvement of beta-cell function in conjunction with glycemic control after medical nutrition therapy in newly-diagnosed type 2 diabetes mellitus.

BACKGROUND: The current study aimed to reveal the correlation of beta-cell function and insulin sensitivity with glycemic control and weight control before and after medical nutrition therapy (MNT) in patients with newly-diagnosed type 2 diabetes mellitus. METHODS: We retrospectively analyzed consecutive 68 patients with newly-diagnosed type 2 diabetes mellitus who started MNT without antihyperglycemic medications and underwent a 75-g oral glucose tolerance test (OGTT) before and after the therapy. Beta-cell function was evaluated by the OGTT-derived disposition index, whereas insulin sensitivity was evaluated by Matsuda's insulin sensitivity index. RESULTS: After 4.0 ± 1.5 months of MNT, mean HbA1c and body mass index significantly decreased from 9.6 ± 1.8% to 7.2 ± 1.0% and from 26.9 ± 4.1 to 25.4 ± 3.7 kg/m2 (both P < 0.001), while the median disposition index and Matsuda's index significantly increased from 0.34 (0.20-0.68) to 0.88 (0.53-1.52) (P < 0.001) and from 4.70 (2.95-5.93) to 5.17 (3.48-6.89) (P = 0.003), respectively. The disposition index was significantly correlated with HbA1c levels both before and after MNT (r = -0.61 and -0.68; both P < 0.001). The magnitude of the correlation after MNT was not different from that before MNT (P = 0.42). Matsuda's index was correlated not with HbA1c levels but with body mass index, both before (r = 0.07 [P = 0.57] and r = -0.58 [P < 0.001]) and after MNT (r = -0.01 [P = 0.95] and r = -0.52 [P < 0.001]). CONCLUSIONS: Beta-cell function was improved in conjunction with glycemic control after MNT in patients with newly-diagnosed type 2 diabetes mellitus. Insulin sensitivity was linked with weight control rather than glycemic control.

Pharmacokinetics, hepatic disposition, and heart tissue distribution of 14 compounds in rat after oral administration of Qi-Li-Qiang-Xin capsule via ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry.

In the present study, a specific and sensitive approach using ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry was developed and validated for the quantitative analysis of 14 constituents in rat plasma, liver, and heart. The method was fully validated and successfully applied to pharmacokinetic, hepatic disposition, and heart tissue distribution studies of 14 compounds after the oral administration of Qi-Li-Qiang-Xin capsule. Ginsenoside Rb1, alisol A, astragaloside IV, and periplocymarin were found to be highly exposed in rat plasma, while toxic components such as hypaconitine, mesaconitine, and periplocin had low circulation levels in vivo. Moreover, sinapine thiocyanate, neoline, formononetin, calycosin, and alisol A exhibited significant liver first-pass effects. Notably, high levels of alisol A, periplocymarin, benzoylmesaconine, and benzoylhypaconine were observed in the heart. Based on high exposure and appropriate pharmacokinetic features in the systemic plasma and heart, astragaloside IV, ginsenoside Rb1, periplocymarin, benzoylmesaconine, benzoylhypaconine, and alisol A can be considered as the main potentially effective components. Ultimately, the results provide relevant information for discovery of effective substances, as well as further anti-heart failure action mechanism investigations of Qi-Li-Qiang-Xin capsule.

Clopidogrel-herb Interactions: A Pharmacokinetic and Pharmacodynamic Assessment in a Rat Model.

BACKGROUND: Herbs usually contain a mixture of biologically active constituents, which can interact with numerous prescribed drugs and alter their safety profiles. OBJECTIVES: The current investigation was aimed to evaluate the effect of commonly used herbal products including black seed (Nigella sativa), garden cress (Lepidium sativum), and fenugreek (Trigonella foenum-graecum) on the pharmacokinetics and pharmacodynamics of clopidogrel using a Wistar rat model. METHODS: A GC-MS analysis revealed the presence of several phytoconstitutents (polyphenols) in the extracts of black seed, garden cress, and fenugreek. These polyphenols have the potential to interfere with clopidogrel effect. Plasma concentrations of clopidogrel were measured at different time points in the absence and presence of the concurrent use of tested herbal products and the pharmacokinetic parameters were calculated. Bleeding time was measured in various groups as a measure of the antiplatelet effect of clopidogrel. RESULTS: Area under the plasma concentration-time curves (AUC0-∞) of clopidogrel were 35.53 ±0.89 µg/ml*h (p<0.05), 26.01 ±0.90 µg/ml*h (p>0.05) and 32.80 ±2.51 µg/ml*h (p<0.05) in the black seed, garden cress and fenugreek group, respectively, compared with that of the control group (27.02 ±0.42 µg/ml*h). Treatment with black seed also caused an increase in clopidogrel Cmax by 31.52% (p<0.05) and with fenugreek by 21.42% (p<0.05); Cmax, did not changed with garden cress treatment (6.48 ±0.15 µg/ml versus 6.12 ±0.21 µg/ml, p>0.05). The pharmacodynamic evaluation of the antiplatelet effect of clopidogrel in the presence of herbal products treatment showed a significant prolongation in the bleeding time from a control baseline by ~22-26%, and by added ~8-12% in reference to clopidogrel therapeutic effect (p<0.05). CONCLUSION: The concurrent use of black seed, fenugreek, or garden cress can alter the pharmacokinetics and pharmacodynamics of clopidogrel to varying degrees due to the presence of various bioactive polyphenols. This is probably due to changes in drug disposition and its antiplatelet action. Further confirmation can determine the clinical relevance of these observations and identify the exact constituents responsible for such activities.

Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions.

Circadian rhythms are ubiquitous phenomena that recur daily in a self-sustaining, entrainable, and oscillatory manner, and orchestrate a wide range of molecular, physiological, and behavioral processes. Circadian clocks are comprised of a hierarchical network of central and peripheral clocks that generate, sustain, and synchronize the circadian rhythms. The functioning of the peripheral clock is regulated by signals from autonomic innervation (from the central clock), endocrine networks, feeding, and other external cues. The critical role played by circadian rhythms in maintaining both systemic and tissue-level homeostasis is well established, and disruption of the rhythm has direct consequence for human health, disorders, and diseases. Circadian oscillations in both pharmacokinetics and pharmacodynamic processes are known to affect efficacy and toxicity of several therapeutic agents. A variety of modeling approaches ranging from empirical to more complex systems modeling approaches have been applied to characterize circadian biology and its influence on drug actions, optimize time of dosing, and identify opportunities for pharmacological modulation of the clock mechanisms and their downstream effects. In this review, we summarize current understanding of circadian rhythms and its influence on physiology, pharmacology, and therapeutic interventions, and discuss the role of chronopharmacometrics in gaining new insights into circadian rhythms and its applications in chronopharmacology.

Effect of Vitamin D Supplementation on Disposition Index in Non-Diabetic Indians with Obesity: A Double-Blind Randomized Placebo-Controlled Trial.

There has been conflicting evidence regarding the potential role of vitamin D in glucose homeostasis. This double-blind randomized placebo-controlled trial was designed to investigate the effect of vitamin D3 supplementation on the disposition index in non-diabetic Indian subjects with obesity. Subjects with obesity [n = 120] were randomized to receive a monthly dose of 120,000 IU of vitamin D3 or matching placebo for 6 months. The primary outcome was a change in disposition index (DI) and secondary outcome measures were change in the homeostatic model assessment of insulin resistance and change in body composition. A total of 101 subjects [50 in the vitamin D group (VITD) and 51 in the Placebo group (PL)] completed the study. The mean baseline serum 25-hydroxyvitamin [25(OH) D] concentration was 11.6 ng/ml. There was no significant difference observed between the two groups in any of the primary or secondary outcomes. However, there were a significant increase in median serum 25(OH) D levels in the VITD group than the PL at 6 months of intervention. The results of the present study suggest that supplementation of vitamin D3 has no additional benefit over placebo on pancreatic ß-cell functions in non-diabetic Indian subjects with obesity. Further larger studies are required to confirm the results of the study. The trial is registered with the Clinical Trials Registry of India, CTRI/2015/04/005727.

Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination.

The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intestine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signaling molecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for maintaining systemic homeostasis. Alterations in the expression and function of OATs contribute to the intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs, and to many pathophysiological conditions. Consequently, the activity of these transporters must be highly regulated to carry out their normal functions. This review will present an update on the recent advance in understanding the cellular and molecular mechanisms underlying the regulation of renal OATs, emphasizing on the post-translational modification (PTM), the crosstalk among these PTMs, and the remote sensing and signaling network of OATs. Such knowledge will provide significant insights into the roles of these transporters in health and disease.

Pharmacokinetic Properties of Orally Administered 4'-Cyano-2'-deoxyguanosine, a Novel Nucleoside Analog Inhibitor of the Hepatitis B Virus, in Viral Liver Injury Model Rats.

A nucleoside analog, 4'-cyano-2'-deoxyguanosine (CdG), which was developed as an inhibitor of the chronic hepatitis B virus (HBV), exhibited a superior antiviral activity against both wild-type and drugs-resistant HBV to marketed nucleoside analogs. In addition to previous pharmacokinetic studies of CdG in healthy rats, this study reports on an evaluation of the pharmacokinetic characteristics of CdG in a rat model of viral liver injury (VLI) induced by treatment with concanavalin A. Following an intravenous administration of CdG at a dose of 1 mg/kg, the plasma concentration profile of CdG in VLI model rats was found to be similar to that of healthy rats with no significant difference in kinetic parameters. However, when CdG was orally administered at a dose of 1 mg/kg, the maximum blood concentration was much lower in VLI model rats than in healthy rats. Interestingly, the amount of residual food in the stomachs in VLI model rats was significantly larger than that in healthy rats, indicating that the adsorption of CdG in the gastrointestinal tract was inhibited in the presence of food as well as other marketed nucleoside analogs. As observed in healthy rats, CdG was largely distributed to the liver compared to the kidney in the VLI model. These results suggest that liver pathology has only a minor effect on the pharmacokinetic properties of CdG, but the influence of food on CdG absorption needs to be considered.

Determination of the antidiabetic chemical basis of Phellodendri Chinensis Cortex by integrating hepatic disposition in vivo and hepatic gluconeogenese inhibition in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Phellodendri Chinensis Cortex (PCC) has been an herb clinically used to treat diabetes, but the chemical basis of its antidiabetic effects has remained unclear. AIM OF THIS STUDY: Based on the efficacy of herbal medicine resulting from the cooperative response of the effective compounds in the target organs with sufficient exposure, the in vivo hepatic disposition and in vitro hepatic gluconeogenesis inhibition were integrated to elucidate the chemical basis for the antidiabetic effect of orally administered PCC from a target organ, liver, perspective. MATERIALS AND METHODS: With a developed and validated HPLC-MS/MS method, three alkaloids and five metabolites were determined in the portal vein plasma, liver, and systemic plasma of rats orally administered PCC. The inhibition of hepatic gluconeogenesis by the eight compounds was evaluated in primary hepatocytes. RESULTS: The in vivo results showed that magnoflorine was present at the highest concentration among the target constituents in the plasma, where berberine showed a low concentration. In contrast, berberine showed the highest concentration in the liver, and its five metabolites exhibited substantial hepatic accumulation. This discrepancy was strongly associated with the hepatic disposition of the compounds. The hepatic disposition prevented the transfer of 96.1% of the phellodendrine, 71.1% of the berberine and 47.5% of the magnoflorine from the portal vein plasma to the systemic plasma, which corresponded to their hepatic distribution and hepatic metabolism. In vitro, berberine, M1, M4 and M5 significantly and dose-dependently inhibited hepatic glucose production. By integrating the hepatic exposure and inhibitory activity data, we estimated that berberine contributed the most (74%) to the total glucose production inhibition of the orally administered PCC decoction, followed by M4 (14%), M1 (11%) and M5 (1%). CONCLUSION: This study was the first to comprehensively describe the pharmacokinetic profiles and hepatic disposition of alkaloids in PCC, and concluded that berberine and its metabolites contributed the most to the total hepatic gluconeogenesis inhibition by orally administered PCC. These results reveal the chemical basis for the antidiabetic effect of orally administered PCC decoction, providing scientific evidence to support the clinical usage of PCC in diabetes treatment.

In vitro, ex vivo and in vivo methods of lung absorption for inhaled drugs.

The assessment and prediction of lung absorption and disposition are an increasingly essential preclinical task for successful discovery and product development of inhaled drugs for both local and systemic delivery. Hence, in vitro, ex vivo and in vivo preclinical methods of lung absorption continue to evolve with several technical, methodological and analytical refinements. As in vitro lung epithelial cell monolayer models, the air-liquid interface (ALI)-cultured Calu-3 cells have most frequently been used, but the NCI-H441 and hAELVi cells have now been proposed as the first immortalized human alveolar epithelial cells capable of forming highly-restricted monolayers. The primary ALI-cultured three-dimensional (3D) human lung cell barriers have also become available; efforts to incorporate aerosol drug deposition into the in vitro lung cell models continue; and stem cell-derived lung epithelial cells and "lung-on-a-chip" technology are emerging. The ex vivo isolated perfused rat lung (IPRL) methods have increasing been used, as they enable the kinetic determination of tissue/organ-level diffusive and membrane protein-mediated absorption and competing non-absorptive loss; the assessment of "pre-epithelial" aerosol biopharmaceutical events in the lung, such as dissolution and release; and the ex vivo-to-in vivo extrapolation and prediction. Even so, in vivo small rodent-based methods have been of mainstay use, while large animal-based methods find an additional opportunity to study region-dependent lung absorption and disposition. It is also exciting that human pharmacokinetic (PK) profiles and systemic exposures for inhaled drugs/molecules may be able to be predicted from these in vivo rodent PK data following lung delivery using kinetic modeling approach with allometric scaling. Overall, the value of these preclinical assessments appears to have shifted more to their translational capability of predicting local lung and systemic exposure in humans, in addition to rationalizing optimal inhaled dosage form and delivery system for drugs/molecules in question. It is critically important therefore to make appropriate selection and timely exploitation of the best models at each stage of drug discovery and development program for efficient progress toward product approval and clinical use.

Predicting Individual Preferences in Mindfulness Techniques Using Personality Traits.

The growing popularity of mindfulness-based interventions (MBIs) has prompted exciting scientific research investigating their beneficial effects on well-being and health. Most mindfulness programs are provided as multi-faceted packages encompassing a set of different mindfulness techniques, each with distinct focus and mechanisms. However, this approach overlooks potential individual differences, which may arise in response to practicing various mindfulness techniques. The present study investigated preferences for four prototypical mindfulness techniques [focused attention (FA), open monitoring (OM), loving-kindness (LK), and body scan (BS)] and identified factors that may contribute to individual differences in these preferences. Participants without prior mindfulness experiences were exposed to each technique through audio-guided instructions and were asked to rank their preferences at the end of all practices. Results indicated that preferences for loving-kindness were predicted by empathy, and that females tended to prefer loving-kindness more than males. Conversely, preferences for open monitoring were predicted by nonreactivity and nonjudgment of present moment experiences. Additionally, higher state mindfulness was detected for individuals' preferred technique relative to other alternatives. These findings suggest that individuals tend to prefer techniques compatible with their personalities, as the predictor variables encompass trait capacities specifically relevant to practicing these techniques. Together, our results suggest the possibility that assessing individual difference and then tailoring MBIs to individual needs could be a useful way to improve intervention effectiveness and subsequent outcomes.

Towards an Individual Differences Perspective in Mindfulness Training Research: Theoretical and Empirical Considerations.

A growing body of research indicates that mindfulness training can have beneficial effects on critical aspects of psychological well-being, cognitive function, and brain health. Although these benefits have been generalized to the population level, individual variability in observed effects of mindfulness training has not been systematically investigated. Research on other similar forms of psychological intervention demonstrates that individual differences are prominent in terms of intervention responsiveness and outcomes. Furthermore, individual characteristics such as personality traits have been shown to play a crucial role in influencing the effects of intervention. In light of these lines of evidence, we review representative work on individual differences in mindfulness training and advocate for an individual difference perspective in mindfulness training research. We discuss relevant empirical evidence of individual differences potentially influencing behavioral outcomes of mindfulness training, focusing on both cognitive function and psychological well-being. Finally, theoretical considerations and potentially fruitful research strategies and directions for studying individual differences in mindfulness training are discussed, including those involving cognitive neuroscience methods.

Pharmacokinetic, bioavailability and tissue distribution study of astilbin in rats.

OBJECTIVE: The purpose of this study is to reveal the pharmacokinetic profiles of astilbin with various doses in rats and investigate the oral absolute bioavailability and tissue distribution of astilbin after oral administration. METHODS: Wistar rats were orally administered astilbin 12, 24 mg/kg and intravenous administered astilbin 6 mg/kg randomly. The concentration of astilbin in rat plasma and various tissue samples was determined by LC-MS/MS method. Noncompartmental pharmacokinetic parameters including AUC and t1/2 were calculated from plasma concentration-time data of astilbin with the DAS 3.0. KEY FINDINGS: After oral administration of astilbin 12 and 24 mg/kg to rats, the oral absolute bioavailability of astilbin were 1.16 ± 0.695% and 1.27 ± 0.379%; the plasma elimination half-lives (t1/2 ) were 101 ± 35.8 and 109 ± 25.3 min, respectively. Astilbin had a rapid absorption and a wide distribution throughout the whole body except liver and fat following oral administration. Astilbin could penetrate the blood-brain barrier of rat. CONCLUSIONS: The oral absolute bioavailability of astilbin is poor because of the low permeability and solubility. Both oral absorption and clearance of astilbin in rats are rapid after oral administration.

Absorption, distribution, metabolism and excretion of molidustat in healthy participants.

The absorption, distribution, metabolism and excretion of molidustat were investigated in healthy male participants. In study 1, a mass balance study, radiolabelled molidustat 25 mg (3.57 MBq) was administered as an oral solution (n = 4). Following rapid absorption, molidustat-related radioactivity was predominantly distributed in plasma rather than in red blood cells. The total recovery of the administered radioactivity was 97.0%, which was mainly excreted renally (90.7%). Metabolite M-1, produced by N-glucuronidation, was the dominant component in plasma (80.2% of the area under the concentration-time curve for total radioactivity) and was primarily excreted via urine (~85% of dose). Only minor amounts of unchanged molidustat were excreted in urine (~4%) and faeces (~6%). Study 2 investigated the absolute bioavailability and pharmacodynamics of molidustat (part 1, n = 12; part 2, n = 16). Orally administered molidustat immediate release tablets had an absolute bioavailability of 59%. Following intravenous administration (1, 5 and 25 mg), total body clearance of molidustat was 28.7-34.5 L/h and volume of distribution at steady state was 39.3-50.0 L. All doses of molidustat transiently elevated endogenous erythropoietin levels, irrespective of the route of administration. Molidustat was considered safe and well tolerated at the administered doses.

P-glycoprotein (MDR1/ABCB1) controls brain accumulation and intestinal disposition of the novel TGF-ß signaling pathway inhibitor galunisertib.

Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-ß) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type mice, but not in single Abcg2-/- mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a-/- mice showed a 1.9-fold higher plasma AUC0-1 hr than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.

Factors in the perceived stress scale differentially associate with mindfulness disposition and executive function among early adolescents.

OBJECTIVES: The first aim was to test the factor structure and item-loadings of the 10-item Perceived Stress Scale (PSS) when administered to early adolescents. The second aim was to examine associations between PSS factors, mindfulness disposition, and executive function. METHODS: We analyzed data collected from 331 students in grade seven (M age=12.4, 48.9% female, 47.1% White, 26.0% Hispanic, 37.8% received free-lunch) classrooms from two ethnically/racially and socio-economically diverse schools. Participants completed paper and pencil self-report measures of stress (PSS), mindfulness disposition (Mindful Awareness Attention Scale, MAAS), and executive function (Behavior Rating Inventory of Executive Function, BRIEF). We tested the statistical association between two factors of the PSS: perceived coping and perceived distress with MAAS and BRIEF. RESULTS: A two-factor model of the PSS, inclusive of perceived coping and perceived distress, fit the data better than a one-dimensional model. MAAS and BRIEF scores were inversely associated with PSS distress scores (ß = -.62, p <.0001 and ß = -.66, p <.0001, respectively), but not PSS coping scores (ß = -.04, p = .21 and ß = -.02, p = .57, respectively) in a model adjusted for sex, race, and socio-economic status. CONCLUSIONS: Two factors in the PSS emerged among early adolescents and differentially associated with mindfulness disposition and executive function to similar magnitudes. Findings encourage future assessment of perceived stress in a more refined manner across developmental stages in order to examine trajectories of perceived distress versus perceived coping in relation to mindfulness disposition and executive function.