Characteristics of symptoms and development of psychological status in late Chinese adolescence.

BACKGROUND: Many late adolescents experience a state of psychological sub-health, requiring early recognition and intervention. This study aims to assess the psychological state of late Chinese adolescents and uncover developmental trend of mental health through network analysis. METHOD: We analyzed data from 9072 Chinese high school adolescents in Shandong Province surveyed in 2020-2021, and divided them into the normal, the suspected, and the abnormal groups based on Symptom Checklist 90 (SCL-90) scores. Network analysis was employed to identify the core symptoms and bridge symptoms across different states. RESULTS: Anxiety and depression were the most central symptoms, without gender differences. Core symptoms, network structure, and network invulnerability varied across different psychological states. The abnormal group exhibited the highest value of natural connectivity, followed by the suspected and normal groups. This pattern extended to bridge networks. While not meeting diagnostic criteria, the suspected group demonstrated abnormalities in network edge invariance and global strength invariance. LIMITATIONS: The cross-sectional design cannot establish causality, and biases in self-report measurements cannot be ignored. CONCLUSION: Compared to traditional scale indicators, network structural characteristics may be a more sensitive assessment indicator.

Physical Exercise Transforms the Topography and Increases the Invulnerability of the Symptom Network of Depression-Anxiety in the Elderly.

BACKGROUND AND OBJECTIVES: Depression and anxiety often co-occur and have worse impacts on the elderly when experienced simultaneously. Although physical exercise may alleviate depression and anxiety, how it affects the specific symptoms is not fully understood. METHODS: A total of 8884 participants was selected from the 2018 CLHLS database. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) and the Generalized Anxiety Disorder Scale-7 (GAD-7) were used to assess depression and anxiety, respectively. Participants were divided into the exercise and the nonexercise groups using propensity score matching to minimize the influence of confounding variables. Depression-anxiety symptom networks were constructed, and network indexes were computed for each group, based on various packages of R. By computing network connectivity, invulnerability simulation was used to investigate the role of physical exercise in network robustness. RESULTS: Both groups had D3 (sad mood), A4 (trouble relaxing) and A2 (uncontrollably worry) as central symptoms. In the exercise group, A1 (nervousness), A3 (too much worry) and D1 (bothered by little things) were the strongest bridge nodes. In the nonexercise group, A1 (nervousness), D1 (bothered by little things) and A4 (trouble relaxing) played this role. Participation in physical exercise decreased the centrality of D9 (cannot get doing) but increased the centrality of A3 (too much worry). Furthermore, the exercise group had higher network invulnerability than the nonexercise group under random attack conditions. CONCLUSIONS: Physical exercise affected core symptoms of depression-anxiety and the interactions of symptoms. Targeting central or bridge nodes may be an effective intervention for alleviating the comorbidity. Increased network invulnerability manifested the positive effects of physical exercise.

Bridging the relationship between physical exercise and mental health in adolescents based on network analysis.

Although physical exercise has been recommended as a useful means of enhancing the mental health of adolescents, the exact mechanisms through which physical exercise plays a role are unclear. Both physical exercise and mental health are complex concepts with multiple facets, and traditional methods may constrain the manifestations of their mapping relationships. This research aimed to find the bridging connections between physical exercise and mental health. Mental health and physical exercise behaviors were assessed using the Symptom Checklist 90 (SCL-90) and the Adolescent Physical Activity Questionnaire (PAQ-A) in 9072 Chinese adolescents, respectively. Network analysis was utilized to construct the mental health-physical exercise network and to analyze the relationships between individual physical exercise behaviors and mental health symptoms. Core and bridging nodes were identified based on expected influence (EI) and bridge expected influence (BEI). Gender differences were also examined. The results revealed specific and distinct pathways between physical exercise and mental health (e.g., winter sports-obsessive-compulsive symptoms, winter sports-phobia). For both males and females, anxiety, depression, interpersonal sensitivity, ball sports, and evening activity were the most central symptoms/behaviors, reflecting their relative significance in their respective associations. The nodes with the highest BEI were obsessive-compulsive symptoms and physical education, showing negative associations with nodes in the other community. Furthermore, in the male group, somatization and winter sports stood out as the most positive bridge nodes. Conversely, in the female group, interpersonal sensitivity and sports games were the most positive bridge nodes. These findings illuminate the pathways linking physical exercise and mental health, supporting the implementation of physical exercise in a more elaborate way.

In vitro and in vivo pharmacokinetic characterization, chiral conversion and PBPK scaling towards human PK simulation of S-MRI-1867, a drug candidate for Hermansky-Pudlak syndrome pulmonary fibrosis.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that affects lysosome-related organelles, often leading to fatal pulmonary fibrosis (PF). The search for a treatment for HPS pulmonary fibrosis (HPSPF) is ongoing. S-MRI-1867, a dual cannabinoid receptor 1 (CB1R)/inducible nitric oxide synthase (iNOS) inhibitor, has shown great promise for the treatment of several fibrotic diseases, including HPSPF. In this study, we investigated the in vitro ADME characteristics of S-MRI-1867, as well as its pharmacokinetic (PK) properties in mice, rats, dogs, and monkeys. S-MRI-1867 showed low aqueous solubility (< 1 µg/mL), high plasma protein binding (>99%), and moderate to high metabolic stability. In its preclinical PK studies, S-MRI-1867 exhibited moderate to low plasma clearance (CLp) and high steady-state volume of distribution (Vdss) across all species. Despite the low solubility and P-gp efflux, S-MRI-1867 showed great permeability and metabolic stability leading to a moderate bioavailability (21-60%) across mouse, rat, dog, and monkey. Since the R form of MRI-1867 is CB1R-inactive, we investigated the potential conversion of S-MRI-1867 to R-MRI-1867 in mice and found that the chiral conversion was negligible. Furthermore, we developed and validated a PBPK model that adequately fits the PK profiles of S-MRI-1867 in mice, rats, dogs, and monkeys using various dosing regimens. We employed this PBPK model to simulate the human PK profiles of S-MRI-1867, enabling us to inform human dose selection and support the advancement of this promising drug candidate in the treatment of HPSPF.

Use of physiological based pharmacokinetic modeling for cross-species prediction of pharmacokinetic and tissue distribution profiles of a novel niclosamide prodrug.

Introduction: Niclosamide (Nc) is an FDA-approved anthelmintic drug that was recently identified in a drug repurposing screening to possess antiviral activity against SARS-CoV-2. However, due to the low solubility and permeability of Nc, its in vivo efficacy was limited by its poor oral absorption. Method: The current study evaluated a novel prodrug of Nc (PDN; NCATS-SM4705) in improving in vivo exposure of Nc and predicted pharmacokinetic profiles of PDN and Nc across different species. ADME properties of the prodrug were determined in humans, hamsters, and mice, while the pharmacokinetics (PK) of PDN were obtained in mice and hamsters. Concentrations of PDN and Nc in plasma and tissue homogenates were measured by UPLC-MS/MS. A physiologically based pharmacokinetic (PBPK) model was developed based on physicochemical properties, pharmacokinetic and tissue distribution data in mice, validated by the PK profiles in hamsters and applied to predict pharmacokinetic profiles in humans. Results: Following intravenous and oral administration of PDN in mice, the total plasma clearance (CLp) and volume of distribution at steady-state (Vdss) were 0.061-0.063 L/h and 0.28-0.31 L, respectively. PDN was converted to Nc in both liver and blood, improving the systemic exposure of Nc in mice and hamsters after oral administration. The PBPK model developed for PDN and in vivo formed Nc could adequately simulate plasma and tissue concentration-time profiles in mice and plasma profiles in hamsters. The predicted human CLp/F and Vdss/F after an oral dose were 2.1 L/h/kg and 15 L/kg for the prodrug respectively. The predicted Nc concentrations in human plasma and lung suggest that a TID dose of 300 mg PDN would provide Nc lung concentrations at 8- to 60-fold higher than in vitro IC50 against SARS-CoV-2 reported in cell assays. Conclusion: In conclusion, the novel prodrug PDN can be efficiently converted to Nc in vivo and improves the systemic exposure of Nc in mice after oral administration. The developed PBPK model adequately depicts the mouse and hamster pharmacokinetic and tissue distribution profiles and highlights its potential application in the prediction of human pharmacokinetic profiles.

Safety evaluations of the processed lateral root of Aconitum carmichaelii Debx. And its hepatotoxicity mechanisms in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The processed lateral root of Aconitum carmichaelii Debx. is known as Fuzi, an extensively used Traditional Chinese Medicine to treat cardiovascular diseases, rheumatism arthritis, bronchitis, pains, and hypothyroidism, etc. Although Chinese Pharmacopeia regulates the safe clinical dosage of Fuzi at 3-15 g/person/day, such recommendation not only lacks bench evidence but also does not differentiate Fuzi with different processing types, such as Heishunpian and Paofupian. AIM OF THE STUDY: The current study aimed to 1) determine No-Observed-Adverse-Effect-Levels of Heishunpian and Paofupian in rats and 2) investigate the related toxicity mechanisms for their safe clinical use. MATERIALS AND METHODS: After giving clinically relevant dosing regimen of Heishunpian/Paofupian to rats, we conducted toxicity assessments including ECG monitoring, histopathological changes and serum biomarkers to detect organ injury. Metabolomic study in the liver revealed changes in endogenous metabolite levels after two-week treatment of Fuzi preparations or its corresponding six toxic alkaloids mixtures. RESULTS: The NOAEL for both bolus and two-week treatments of Heishunpian and Paofupian in rats was designated to be 7.5 g/kg and 15 g/kg, respectively. Corresponding recommended doses in humans were 7.5-25 g/person/day for Heishunpian and 15-50 g/person/day for Paofupian. Metabolic profiles revealed more significant alterations in endogenous substances from rats receiving the two Fuzi preparations than their corresponding toxic alkaloids mixtures. Upregulation of bile acid pathway could be responsible for Fuzi induced liver injury. CONCLUSIONS: Compared to the current maximum recommended dose, our suggested upper limit of guided dose for Heishunpian was comparable, whereas that for Paofupian could be further elevated. Both C19-diterpenoid alkaloids and co-occurring components in Fuzi preparations contributed to their hepatotoxicity via upregulation of bile acid pathway.

Preclinical Pharmacokinetics and In Vitro Properties of GS-441524, a Potential Oral Drug Candidate for COVID-19 Treatment.

Preclinical pharmacokinetics (PK) and In Vitro ADME properties of GS-441524, a potential oral agent for the treatment of Covid-19, were studied. GS-441524 was stable in vitro in liver microsomes, cytosols, and hepatocytes of mice, rats, monkeys, dogs, and humans. The plasma free fractions of GS-441524 were 62-78% across all studied species. The in vitro transporter study results showed that GS-441524 was a substrate of MDR1, BCRP, CNT3, ENT1, and ENT2; but not a substrate of CNT1, CNT2, and ENT4. GS-441524 had a low to moderate plasma clearance (CLp), ranging from 4.1 mL/min/kg in dogs to 26 mL/min/kg in mice; the steady state volume distribution (Vdss) ranged from 0.9 L/kg in dogs to 2.4 L/kg in mice after IV administration. Urinary excretion appeared to be the major elimination process for GS-441524. Following oral administration, the oral bioavailability was 8.3% in monkeys, 33% in rats, 39% in mice, and 85% in dogs. The PK and ADME properties of GS-441524 support its further development as an oral drug candidate.

Important roles of transporters in the pharmacokinetics of anti-viral nucleoside/nucleotide analogs.

INTRODUCTION: Nucleoside analogs are an important class of antiviral agents. Due to the high hydrophilicity and limited membrane permeability of antiviral nucleoside/nucleotide analogs (AVNAs), transporters play critical roles in AVNA pharmacokinetics. Understanding the properties of these transporters is important to accelerate translational research for AVNAs. AREAS COVERED: The roles of key transporters in the pharmacokinetics of 25 approved AVNAs were reviewed. Clinically relevant information that can be explained by the modulation of transporter functions is also highlighted. EXPERT OPINION: Although the roles of transporters in the intestinal absorption and renal excretion of AVNAs have been well identified, more research is warranted to understand their roles in the distribution of AVNAs, especially to immune privileged compartments where treatment of viral infection is challenging. P-gp, MRP4, BCRP, and nucleoside transporters have shown extensive impacts in the disposition of AVNAs. It is highly recommended that the role of transporters should be investigated during the development of novel AVNAs. Clinically, co-administered inhibitors and genetic polymorphism of transporters are the two most frequently reported factors altering AVNA pharmacokinetics. Physiopathology conditions also regulate transporter activities, while their effects on pharmacokinetics need further exploration. Pharmacokinetic models could be useful for elucidating these complicated factors in clinical settings.

Protective effect of Glechoma hederacea extract against gallstone formation in rodent models.

BACKGROUND: Our current study aimed to evaluate the effect of an Glechoma hederacea extract (Hitrechol®) in normal rats and gallstone diseased mice to explore its underlying mechanisms. Normal rats and C57BL/6 mice with/without cholesterol gallstone were used in this study. METHODS: To monitor the effect of Hitrechol® on bile secretion, bile flow rates at 15 min interval until 2 h post-dosing in normal rats treated with vehicle and Hitrechol® were compared using multiple t-test with a p < 0.05 considered as statistically significant different. To further evaluate the effect of Hitrechol® against the development of gallstone in lithogenic diet treated mice, mice were treated with vehicle or Hitrechol® (QD-once daily or TID-three times daily) for 3 weeks followed by comparing the levels of bile composition among the treatment groups. In addition, the anti-oxidative biomarkers in liver and anti-inflammatory biomarkers in serum were detected and compared among all the treatment groups to evaluate the hepato-protective effect of Hitrechol®. The obtained levels of biomarkers and bile composition were compared among different treatment groups using one-way ANOVA tests followed by Tukey's multiple comparisons with p < 0.05 considered as statistically significant. RESULTS: Despite no significant impact on the bile flow rate, Hitrechol® TID treatment dramatically decreased size and amount of gallstone crystals and total cholesterol level (p < 0.05), as well as total bile acid (p < 0.05) and several types of bile acid (p < 0.05) levels in gallstone disease model mice. Hitrechol® TID treatment could significantly decrease the frequencies of hepatocyte necrosis and lipid aggregation notably as well as increase the antioxidant enzyme level (p < 0.05) in the liver. CONCLUSIONS: Our findings for the first time demonstrated the beneficial effect of Hitrechol® against gallstone via its litholytic, liver-protective and antioxidant activities.

Protein Binding and Population Pharmacokinetics of Dexmedetomidine after Prolonged Infusions in Adult Critically Ill Patients.

PURPOSE: Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist with high protein binding of 94%. Critical illness may affect protein binding and the pharmacokinetic (PK) parameters of many drugs, including DEX. In critically ill patients receiving prolonged infusions of DEX, there is little information documenting the relationship between key pathophysiologic factors and DEX protein binding or PK parameters. The purpose of this study was to characterize the protein binding and PK profile of prolonged DEX infusion in critically ill patients. METHODS: Critically ill, adult intensive care unit patients at a university hospital in Hong Kong were studied. The association between the pathophysiologic changes of critical illness and protein binding was evaluated using a generalized estimating equation. A population pharmacokinetic model to establish the PK profile of DEX was developed, and key pathophysiologic covariate effects of severity of illness, organ dysfunction measures, and altered protein binding on DEX PK parameters in this critically ill population were evaluated. FINDINGS: A total of 22 critically ill patients and 1 healthy control were included. Mean protein binding of DEX in the critically ill patients was 90.4% (95% CI, 89.1-91.7), which was 4% lower than that in the healthy control. The PK data were adequately described by a 2-compartment model. The estimated population mean (relative standard error [RSE]) values of systemic clearance (CL), volume of distribution of the central compartment (V2), intercompartmental clearance (Q), and Vd in the peripheral compartment (V3) were 38.6 (11.7) L/h, 32.1 (46.1) L, 114.5 (58.3) L/h and 95.1 (30.6) L, respectively. The corresponding estimated interindividual variability expressed as CV% (RSE) was 52.4 (23.8) for CL, 172.9 (19.3) for V2, 123.7 (33.7) for Q, and 106 (39.9) for V3. No significant explanatory pathophysiologic covariates were identified. IMPLICATIONS: Although a marginally significant reduction of protein binding in critically ill patients was demonstrated, the magnitude of the difference was unlikely to be of clinical significance. Higher alanine aminotransferase concentration was associated with decreased protein binding. No significant pathophysiologic covariates were associated with the observed PK parameters. The high interindividual variability of PK parameters supports the current practice of dose titration to ensure the desired clinical effects of DEX infusion in the intensive care unit setting.

Overview of Pharmacokinetics and Liver Toxicities of Radix Polygoni Multiflori.

Radix Polygoni Multiflori (RPM), a traditional Chinese medicine, has been used as a tonic and an anti-aging remedy for centuries. However, its safe and effective application in clinical practice could be hindered by its liver injury potential and lack of investigations on its hepatotoxicity mechanism. Our current review aims to provide a comprehensive overview and a critical assessment of the absorption, distribution, metabolism, excretion of RPM, and their relationships with its induced liver injury. Based on the well-reported intrinsic liver toxicity of emodin, one of the major components in RPM, it is concluded that its plasma and liver concentrations could attribute to RPM induced liver injury via metabolic enzymes alteration, hepatocyte apoptosis, bile acids homeostasis disruption, and inflammatory damage. Co-administered 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside in RPM and other drugs/herbs could further aggravate the hepatotoxicity of emodin via enhancing its absorption and inhibiting its metabolism. To ensure the safe clinical use of RPM, a better understanding of the toxicokinetics and effect of its co-occurring components or other co-administered drugs/herbs on the pharmacokinetics of emodin is warranted.

Is it safe to take Radix Salvia Miltiorrhiza - Radix Pueraria Lobate product with warfarin and aspirin? A pilot study in healthy human subjects.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Salvia Miltiorrhiza (Danshen) and Radix Pueraria Lobate (Gegen) are officially listed in the Chinese Pharmacopoeia and have long been used together as a Compound Chinese Traditional Medicine (CCTM) for treatment of coronary heart diseases, which are often co-administered with aspirin or warfarin to patients suffering from cardiovascular diseases. AIM OF STUDY: Since significant pharmacokinetic and pharmacodynamic interactions between Danshen-Gegen (DG) formula and aspirin/warfarin have been observed in our previous rat studies, the current study was proposed aiming to further verify such pharmacokinetic and pharmacodynamic interactions in healthy human subjects and explore related mechanisms. MATERIALS AND METHODS: A 5-day, multiple dose, five-session clinical trial has been carried out (n = 14) with 2-week washout periods between sessions, during which the subjects would receive different combinations of the medications. Plasma samples were collected for pharmacokinetic evaluation, and whole blood samples were collected for pharmacodynamic evaluation. In addition, an in-vitro mechanistic study is conducted to investigate the role of danshensu on the anti-thrombotic and anti-platelet aggregation effects of warfarin and aspirin respectively. RESULTS: Significant pharmacokinetic and pharmacodynamic herb-drug interactions were observed in healthy human subjects. pharmacokinetically, co-administration of DG with aspirin or warfarin could lead to a moderately increased AUC0→t of aspirin and a decreased AUC0→t of 7-hydroxyl warfarin respectively. The systemic exposure of danshensu (DSS, the marker component of DG) would be significantly increased after co-administration with warfarin. Pharmacodynamically, a reduction in systemic thromboxane B2 concentration was noticed after administration of DG with aspirin, which could be associated with the increased systemic exposure of aspirin and the synergistic effect of danshensu, aspirin and salicylic acid on cyclooxygenase (COX) inhibition. An offset on the warfarin induced soluble thrombomodulin induction was observed after its co-administration with DG, which could be partially attributed to the COX-2 inhibition effect of danshensu. CONCLUSION: Our results indicated that co-administration of DG with aspirin/warfarin would lead to significant pharmacokinetic and pharmacodynamic herb-drug interactions in healthy human subjects.

Reduced systemic exposure and brain uptake of donepezil in rats with scopolamine-induced cognitive impairment.

1. Donepezil (DPZ) is an acetylcholinesterase (AchE) inhibitor used in the mild to moderately severe Alzheimer's disease. Among its major metabolites, 6-O-desmethyl DPZ (6-DDPZ), 5-O-desmethyl DPZ (5-DDPZ) and DPZ N-oxide, the anti-AchE activities of 5-DDPZ and DPZ N-oxide have never been clearly identified before. Besides, there is no report on simultaneous determination of DPZ and its three metabolites in the brain, thus their uptake in hippocampus and cortex are unknown. Therefore, the current studies are proposed aiming to: (1) investigate the anti-AchE activities and brain uptake of DPZ and its three metabolites and (2) compare their pharmacokinetics and brain uptake between normal and scopolamine-induced rats.2. DPZ and its three metabolites demonstrated anti-AchE activities with the IC50 in the order of DPZ (7.20 × 10-2 µM), 6-DDPZ (1.14 × 10-1 µM), 5-DDPZ (4.03 × 10-1 µM) and DPZ N-oxide (1.61 µM). They were also evenly distributed in the brain and retained much longer in the brain than that in plasma in normal rats.3. Compared to normal rats, Cmax, AUC0→24h and AUC0→∞ of DPZ were reduced by 52.0%, 31.2% and 30.1%, respectively; Tmax of DPZ and its three metabolites were prolonged and their brain uptake were decreased in scopolamine-induced rats, suggesting the potential reduced absorption of DPZ.

Absorption difference between hepatotoxic pyrrolizidine alkaloids and their N-oxides - Mechanism and its potential toxic impact.

ETHNOPHARMACOLOGICAL RELEVANCE: Pyrrolizidine alkaloids (PAs) are a group of phytotoxins widely present in about 3% of flowering plants. Many PA-containing herbal plants can cause liver injury. Our previous studies demonstrated that PA N-oxides are also hepatotoxic, with toxic potency much lower than the corresponding PAs, due to significant differences in their toxicokinetic fates. AIM OF STUDY: This study aimed to investigate the oral absorption of PAs and PA N-oxides for better understanding of their significant differences in toxicokinetics and toxic potency. MATERIALS AND METHODS: The oral absorption of PAs and PA N-oxides in rats and in rat in situ single pass intestine perfusion model was investigated. The intestinal permeability and absorption mechanisms of five pairs of PAs and PA N-oxides were evaluated by using Caco-2 monolayer model. RESULTS: The plasma concentrations of total PAs and PA N-oxides within 0-60 min were significantly lower in rats orally treated with a PA N-oxide-containing herbal alkaloid extract than with a PA-containing herbal alkaloid extract at the same dose, indicating that the absorption of PA N-oxides was lower than that of PAs. Using the rat in situ single pass intestine perfusion model, less cumulative amounts of retrorsine N-oxide in mesenteric blood were observed compared to that of retrorsine. In Caco-2 monolayer model, all five PAs showed absorption with Papp AtoB values [(1.43-16.26) × 10-6 cm/s] higher than those of corresponding N-oxides with Papp AtoB values lower than 1.35 × 10-6 cm/s. A further mechanistic study demonstrated that except for senecionine N-oxide, retrorsine N-oxide, and lycopsamine N-oxide, all PAs and PA N-oxides investigated were absorbed via passive diffusion. While, for these 3 PA N-oxides, in addition to passive diffusion as their primary transportation, efflux transporter-mediated active transportation was also involved but to a less extent with the efflux ratio of 2.31-3.41. Furthermore, a good correlation between lipophilicity and permeability of retronecine-type PAs and their N-oxides with absorption via passive diffusion was observed, demonstrating that PAs have a better oral absorbability than that of the corresponding PA N-oxides. CONCLUSION: We discovered that among many contributors, the lower intestinal absorption of PA N-oxides was the initiating contributor that caused differences in toxicokinetics and toxic potency between PAs and PA N-oxides.

Current trends in drug metabolism and pharmacokinetics.

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

Pharmacokinetic interactions between metformin and berberine in rats: Role of oral administration sequences and microbiota.

AIMS: Considering the potential oral administration sequences and role of microbiota for metformin (MET) and berberine (BBR) during anti-diabetic treatments, the current study aimed to investigate the pharmacokinetic interactions between MET and BBR in rats after oral administration at different sequences and impacts of microbiota on such interactions. MAIN METHODS: Sprague-Dawley rats were divided into five groups as per what was orally administered to them: MET (G1)/BBR (G2) at 200 mg/kg, BBR 2-hour (h) after dosing MET (G3), MET 2-h after dosing BBR (G4) or MET with BBR at the same time (G5) followed by monitoring their pharmacokinetic profiles. Further in vitro incubations mimicking the above five treatments in rat intestinal content (G1R-G5R), human fecalase (G1H-G5H) and selected bacteria (G1B-G5B) were conducted for both MET and BBR (10 µg/ml for G1R/H-G5R/H and 50 µM for G1B-G5B) up to 24-h. Concentrations of MET and BBR were analyzed by LC/MS/MS. KEY FINDINGS: Although BBR was barely measurable in vivo, it significantly increased systemic exposure of MET in G3/G4. Consistent with pharmacokinetic findings, sequential in vitro incubations of MET and BBR in both rat intestinal content and human fecalase demonstrated significant increase on MET persisted after 24-h incubation in G3R/H & G4R/H. Moreover, post-dose (G3B) and pre-dose (G4B) of BBR decreased the MET degradation significantly in most selected bacteria. SIGNIFICANCE: Our finding for the first time demonstrated the significant effect of sequential co-administration of BBR and MET on their pharmacokinetic interactions, which could be related to their microbiota mediated metabolisms in gastrointestinal tract (GI).

Reduced Systemic and Brain Exposure with Inhibited Liver Metabolism of Carbamazepine After Its Long-Term Combination Treatment with Piperine for Epilepsy Control in Rats.

Carbamazepine (CBZ) with piperine, the active ingredient in black pepper, which is omnipresent in food and may be potentially used for epilepsy control owing to its anticonvulsant effects, can be coadministered to epileptic patients. Since piperine has previously demonstrated its inhibition of the CYP3A-mediated metabolism of CBZ to carbamazepine-10,11-epoxide (CBZE), the present study aimed to investigate the impact of piperine on CBZ pharmacokinetics (PKs) in rats and pharmacodynamics in zebrafish and mouse acute seizure models. Plasma and brain PKs were studied in rats after a single-dose or 2-week combined oral administration of piperine (3.5/35 mg/kg, q.d.) and CBZ (40 mg/kg, t.i.d.) by blood sampling and brain microdialysis. Although no PK change was noticed after a single coadministration, significantly decreased plasma and brain concentrations of CBZ and CBZE with inhibited rat liver Cyp3a2 were demonstrated after long-term combined administration. Our developed compartmental model for the PK characterization of CBZ and CBZE in the blood and brain further estimated that coadministration with high-dose piperine could lead to decreases of 26%, 35%, and 38% in bioavailability, metabolism, and brain uptake of CBZ, respectively. Regardless of the PK changes, a limited impact on the antiepileptic effect of CBZ was found after the coadministration of CBZ and piperine in the tested seizure models. In conclusion, single-dose cotreatment of CBZ and piperine did not result in any significant PK or pharmacodynamic interactions, whereas their long-term cotreatment could lead to inhibited liver metabolism and the markedly reduced systemic and brain exposure of CBZ and CBZE.

Large inter-individual variability in pharmacokinetics of dexmedetomidine and its two major N-glucuronides in adult intensive care unit patients.

Dexmedetomidine (DMTD), an α2-adrenoceptor agonist, is commonly used for sedation and analgesia in intensive care unit (ICU) patients. The primary plasma metabolites of DMTD are its direct N-glucuronides, namely N3-glucuronide of dexmedetomidine (DG1) and N1-glucuronide of dexmedetomidine (DG2), accounting for 41% of DMTD metabolism in healthy volunteers. Since variations on the extent of N-glucuronidation could be one of the key factors contributing to the high interpatient differences of DMTD pharmacokinetics in ICU patients and its subsequent sedative effect. In order to fully evaluate the N-glucuronidation of DMTD in ICU patients, the current study aimed to develop a LC/MS/MS method to simultaneously quantify DMTD and its two major N-glucuronides, DG1 and DG2, in plasma samples and describe their pharmacokinetics in adult ICU patients. Solid-phase extraction cartridges were used to effectively extract DMTD, DG1 and DG2 from 0.4 mL plasma with the internal standard tolazoline. The method was applied in determining the pharmacokinetic profiles of DMTD, DG1, and DG2 in nine ICU patients (mean ±â€¯SD admission severity of illness APACHE II score 23 ±â€¯5) receiving dexmedetomidine infusion for 667 to 3518 min. Under the optimized LC/MS/MS conditions, no endogenous interference from blank plasma was observed. The linear range was 25-5000 pg/mL for DMTD, 50-5000 pg/mL for DG1, and 56-2800 pg/mL for DG2 with good linearity (r2 ranges: 0.997-0.999, 0.993-0.999, and 0.993-0.998 for DMTD, DG1 and DG2 respectively). The precision, accuracy and the stability of DMTD, DG1, and DG2 at their quality control concentrations complied with Food and Drug Administration bioanalytical criteria. The assay was applied in determining the pharmacokinetic profiles of DMTD, DG1, and DG2 in nine ICU patients. The range of AUCDG1/AUCDMTD (from 0.40 to 2.20) and AUCDG2/AUCDMTD (from 0.15 to 2.02) suggested large inter-patient differences in the glucuronidation of DMTD. The mean AUC0-∞ ratio between total glucuronides and DMTD in ICU patients receiving infusions (2.09, range 0.55-4.16) appeared lower than the reported value in healthy volunteers receiving bolus intravenous injection (2.86). This description of the pharmacokinetics of DMTD, DG1, and DG2 in ICU patients is novel and suggests that pathophysiological changes in critically ill patients may have potential to decrease the glucuronidation of DMTD.

Intestinal and hepatic biotransformation of pyrrolizidine alkaloid N-oxides to toxic pyrrolizidine alkaloids.

Pyrrolizidine alkaloids (PAs) are among the most significant groups of phytotoxins present in more than 6000 plants in the world. Hepatotoxic retronecine-type PAs and their corresponding N-oxides usually co-exist in plants. Although PA-induced hepatotoxicity is known for a long time and has been extensively studied, the toxicity of PA N-oxide is rarely investigated. Recently, we reported PA N-oxide-induced hepatotoxicity in humans and rodents and also suggested the association of such toxicity with metabolic conversion of PA N-oxides to the corresponding toxic PAs. However, the detailed biochemical mechanism of PA N-oxide-induced hepatotoxicity is largely unknown. The present study investigated biotransformation of four representative cyclic retronecine-type PA N-oxides to their corresponding PAs in both gastrointestinal tract and liver. The results demonstrated that biotransformation of PA N-oxides to PAs was mediated by both intestinal microbiota and hepatic cytochrome P450 monooxygenases (CYPs), in particular CYP1A2 and CYP2D6. Subsequently, the formed PAs were metabolically activated predominantly by hepatic CYPs to form reactive metabolites exerting hepatotoxicity. Our findings delineated, for the first time, that the metabolism-mediated mechanism of PA N-oxide intoxication involved metabolic reduction of PA N-oxides to their corresponding PAs in both intestine and liver followed by oxidative bioactivation of the resultant PAs in the liver to generate reactive metabolites which interact with cellular proteins leading to hepatotoxicity. In addition, our results raised a public concern and also encouraged further investigations on potentially remarkable variations in PA N-oxide-induced hepatotoxicity caused by significantly altered intestinal microbiota due to individual differences in diets, life styles, and medications.

Tissue Accumulations of Toxic Aconitum Alkaloids after Short-Term and Long-Term Oral Administrations of Clinically Used Radix Aconiti Lateralis Preparations in Rats.

Although Radix Aconiti Lateralis (Fuzi) is an extensively used traditional Chinese medicine with promising therapeutic effects and relatively well-reported toxicities, the related toxic aconitum alkaloid concentrations in major organs after its short-term and long-term intake during clinical practice are still not known. To give a comprehensive understanding of Fuzi-induced toxicities, current study is proposed aiming to investigate the biodistribution of the six toxic alkaloids in Fuzi, namely Aconitine (AC), Hypaconitine (HA), Mesaconitine (MA), Benzoylaconine (BAC), Benzoylhypaconine (BHA) and Benzoylmesaconine (BMA), after its oral administrations at clinically relevant dosing regimen. A ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous quantification of six toxic alkaloids in plasma, urine and major organs of Sprague Dawley rats after oral administrations of two commonly used Fuzi preparations, namely Heishunpian and Paofupian, at their clinically relevant dose for single and 15-days. Among the studied toxic alkaloids and organs, BMA demonstrated the highest concentrations in all studied organs with liver containing the highest amount of the studied alkaloids, indicating their potential hepatotoxicity. Moreover, tissue accumulation of toxic alkaloids after multiple dose was observed, suggesting the needs for dose adjustment and more attention to the toxicities induced by chronic use of Fuzi in patients.