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This study investigated the preventive potential of whey protein fermented with Lacticaseibacillus rhamnosus IM36 (FWP) against muscle atrophy induced by dexamethasone (DEX). FWP exhibited enhanced antioxidant activities compared with those of unfermented whey protein, effectively suppressing DEX-induced reactive oxygen species production. FWP was treated before the administration of 100 µM DEX on C2C12 myotubes and compared to unfermented whey (WP). DEX significantly inhibited myotube viability and muscle protein synthesis and enhanced degradation. FWP exhibited a dose-dependent attenuation of cell viability loss compared with that of WP. Additionally, FWP stimulated the formation of myotubes and muscle protein synthesis by upregulating myogenesis and insulin-like growth factor-1 expression. Furthermore, FWP significantly attenuated forkhead box protein O3a-mediated ubiquitin ligases and autophagy of lysosomes activated by DEX, inhibiting pathways that lead to muscle protein breakdown. These findings suggest that FWP enhances antioxidant activity and prevented DEX-induced muscle atrophy by regulating muscle protein homeostasis. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-024-01640-x.
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BACKGROUND: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations. OBJECTIVES: The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens. METHOD: The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model. RESULTS: The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78-2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained. CONCLUSION: This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population. CLINICAL TRIAL REGISTRATION: The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.
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4-tert-octylphenol (4-tert-OP) is an ecologically hazardous substance, and exposure to it in the environment has been consistently reported in the past. Despite the hazards and widespread exposure to 4-tert-OP, tools for scientific assessment of 4-tert-OP exposure risk level in humans are lacking. The main purpose of this study was to develop a physiologically-based-toxicokinetic (PBTK) model for 4-tert-OP and to perform quantitative risk assessment of 4-tert-OP in various population groups using the established model. Based on the results of toxicokinetic experiments on male rats, the PBTK model for 4-tert-OP was established and verified, and this was converted to a model for humans through interspecies extrapolation. Based on the previously reported no-observed-adverse-effect-levels for rats, it was possible to estimate the 4-tert-OP reference dose in humans through reverse dosimetry using the model. Biomonitoring data derived from various population groups were applied to the human PBTK model to calculate external exposures and margin of safety for 4-tert-OP for each population group. The PBTK model established in this study adequately explained the toxicokinetic experimental values at acceptable levels and was able to quantitatively predict the 4-tert-OP exposure level in the testes related to male reproductive toxicity. In addition, the degree of external exposure to 4-tert-OP could be scientifically estimated based on biomonitoring values derived from various biological matrices. The reference doses for systemic and reproductive toxicity caused by 4-tert-OP in male humans were calculated to be 0.16 and 1.12 mg/kg/day, respectively. The mean external exposure to 4-tert-OP in each population group estimated based on plasma and urine biomonitoring data was 0.04-66.24 mg/kg/day, showing very large exposure diversity between groups. Exposure risks to 4-tert-OP in populations ranged from safe to risky, suggesting the need for continued monitoring and risk management of 4-tert-OP worldwide. This study provides valuable scientific insight regarding the 4-tert-OP human risk assessment.
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Cefaclor is a substrate of human-peptide-transporter-1 (PEPT1), and the impact of inter-individual pharmacokinetic variation due to genetic polymorphisms of solute-carrier-family-15-member-1 (SLC15A1) has been a topic of great debate. The main objective of this study was to analyze and interpret cefaclor pharmacokinetic variations according to genetic polymorphisms in SLC15A1 exons 5 and 16. The previous cefaclor bioequivalence results were integrated with additional SLC15A1 exons 5 and 16 genotyping results. An analysis of the structure-based functional impact of SLC15A1 exons 5 and 16 genetic polymorphisms was recently performed using a PEPT1 molecular modeling approach. In cefaclor pharmacokinetic analysis results according to SLC15A1 exons 5 and 16 genetic polymorphisms, no significant differences were identified between genotype groups. Furthermore, in the population pharmacokinetic modeling, genetic polymorphisms in SLC15A1 exons 5 and 16 were not established as effective covariates. PEPT1 molecular modeling results also confirmed that SLC15A1 exons 5 and 16 genetic polymorphisms did not have a significant effect on substrate interaction with cefaclor and did not have a major effect in terms of structural stability. This was determined by comprehensively considering the insignificant change in energy values related to cefaclor docking due to point mutations in SLC15A1 exons 5 and 16, the structural change in conformations confirmed to be less than 0.05 Å, and the relative stabilization of molecular dynamic simulation energy values. As a result, molecular structure-based analysis recently suggested that SLC15A1 exons 5 and 16 genetic polymorphisms of PEPT1 were limited to being the main focus in interpreting the pharmacokinetic diversity of cefaclor.
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Cefaclor , Transportador de Péptidos 1 , Humanos , Transportador de Péptidos 1/genética , Transportador de Péptidos 1/metabolismo , Cefaclor/farmacocinética , Exones/genética , Genotipo , Polimorfismo Genético , Antibacterianos/farmacocinética , Polimorfismo de Nucleótido Simple , Modelos MolecularesRESUMEN
Cannabidiol (CBD) is a non-psychoactive substance that exerts numerous pharmacological benefits, including anti-inflammatory and antioxidant properties. It has received attention as a useful substance for the treatment of intractable pain, seizures, and anxiety, and related clinical trials have continued. However, the CBD pharmacokinetic results between reports are highly variable, making it difficult to clearly identify the pharmacokinetic properties of CBD. The main purpose of this study was to identify CBD clinical pharmacokinetic properties through meta-analysis. In particular, we sought to derive valid, interpretable independent variables and interpret their pharmacokinetic parameter correlations in relation to the large inter-individual and inter-study variability in CBD pharmacokinetics. For this study, CBD-related clinical trial reports were extensively screened and intercomparisons were performed between internal data sets through systematic classification and extraction of pharmacokinetic parameter values. The candidate independent variables associated with interpretation of CBD pharmacokinetic diversity established and explored in this study were as follows: diet, tetrahydrocannabinol (THC) combination, sample matrix type, liver and renal function, exposure route, dosage form, CBD exposure dose, cannabis smoking frequency, multiple exposure. The results of this study showed that CBD pharmacokinetics were influenced (increased plasma exposure by approximately 2-5 times) by diet immediately before or during CBD exposure, and that THC was not expected to have an antagonistic effect on the CBD absorption. The influence of changes in liver function would be significant in CBD pharmacokinetic diversity. Due to decreased liver function, the plasma exposure of CBD increased 2.57-5.15 times compared to healthy adults, and the half-life and clearance showed a 2.58-fold increase and a 5.15-fold decrease, respectively. CBD can be rapidly absorbed into the body (time to reach maximum concentration within 3.18 h) by oral, transdermal, and inhalation exposures, and lipid emulsification and nanoformulation of CBD will greatly improve CBD bioavailability (up to approximately 2 times). The pharmacokinetics of CBD generally follow linear kinetic characteristics. The importance of this study is that it suggests key factors that should be considered in terms of pharmacokinetics in further clinical trials and formulations of CBD in the future.
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Due to the inevitable differences in physiological and/or genetic factors between genders, the possibility that differences in pharmacokinetics between genders may occur when exposed to the same dose of the same drug is subject to reasonable inference and suspicion. Nevertheless, a significant number of medicines still rely on empirical usage and uniform clinical application without consideration of inter-individual diversity factors. In particular, in the pharmacokinetic diversity of medicines related to central nervous system (CNS) activity, consideration of gender factors and access to comparative analysis are very limited. The purpose of this study was to conduct an integrated analysis and review of differences in pharmacokinetics between genders that have not been specifically reported to date for medicines related to CNS effects, which are a group of drugs with relatively significant concerns about systemic side effects. This study was accessible through extensive data collection and analyzes using a web-based scientific literature search engine of pharmacokinetic results of CNS-related drugs performed on humans, taking gender into account. As a result, significant differences in pharmacokinetics between genders were identified for many drugs related to CNS. And most of the pharmacokinetic differences between genders suggested a higher in vivo exposure in females. This study suggests that consideration of gender factors cannot be ignored and will be an important point of interest in the precision medicine application of CNS-related medicines.
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Levodropropizine is a non-narcotic, non-centrally acting antitussive that inhibits the cough reflex triggered by neuropeptides. Despite the active clinical application of levodropropizine, the exploration of its inter-individual pharmacokinetic diversity and of factors that can interpret it is lacking. The purpose of this study was to explore effective covariates associated with variation in the pharmacokinetics of levodropropizine within the population and to perform an interpretation of covariate correlations from a therapeutic perspective. The results of a levodropropizine clinical trial conducted on 40 healthy Korean men were used in this pharmacokinetic analysis, and the calculated pharmacokinetic and physiochemical parameters were screened for effective correlations between factors through heatmap and linear regression analysis. Along with basic compartmental modeling, a correlation analysis was performed between the model-estimated parameter values and the discovered effective candidate covariates for levodropropizine, and the degree of toxicity and safety during the clinical trial of levodropropizine was quantitatively monitored, targeting the hepatotoxicity screening panel. As a result, eosinophil level and body surface area (BSA) were explored as significant (p-value < 0.05) physiochemical parameters associated with the pharmacokinetic diversity of levodropropizine. Specifically, it was confirmed that as eosinophil level and BSA increased, levodropropizine plasma exposure increased and decreased, respectively. Interestingly, changes in an individual's plasma exposure to levodropropizine depending on eosinophil levels could be interpreted as a therapeutic advantage based on pharmacokinetic benefits linked to the clinical indications for levodropropizine. This study presents effective candidate covariates that can explain the inter-individual pharmacokinetic variability of levodropropizine and provides a useful perspective on the first-line choice of levodropropizine in the treatment of inflammatory respiratory diseases.
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4-tert-octylphenol (4-tert-OP) is a potentially harmful substance, which is found widely in the environment. Nevertheless, information on the in vivo toxicokinetics of 4-tert-OP is lacking, and quantitative risk assessment studies are urgently needed. Therefore, we aimed to quantitatively identify differences in the toxicokinetics of 4-tert-OP and its distribution among tissues between sexes. To this end, following exposure of male and female rats to 10 or 50 mg/kg 4-tert-OP orally and 4 or 8 mg/kg 4-tert-OP intravenously, we conducted a quantitative analysis of samples using ultra-high performance liquid chromatography-tandem mass spectrometry. The results revealed that the 4-tert-OP plasma concentration profiles differed between sexes; however, systemic absorption of 4-tert-OP through the gastrointestinal tract occurred within 0.5 h of exposure in both sexes. Although small, the excretion percentage of 4-tert-OP in urine and feces was lower in males than females (0.06-0.08% vs. 0.82-1.11% of exposure). Significant sex differences were also confirmed in the tissue distribution patterns of 4-tert-OP, and overall, the average tissue distribution in males was lower than that in females. The distribution of 4-tert-OP to liver, adipose, spleen, kidney, brain, and lung in both sexes was predominant. A covariate exploration modeling approach revealed that sex explained the differences in 4-tert-OP toxicokinetics between sexes. These significant differences in the toxicokinetics and tissue distribution of 4-tert-OP between sexes will be important for the scientific precision human risk assessment of 4-tert-OP.
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Fenoles , Caracteres Sexuales , Masculino , Ratas , Humanos , Femenino , Animales , Fenoles/toxicidad , Fenoles/análisis , Hígado/química , Bazo , ToxicocinéticaRESUMEN
Currently, there is insufficient information on the variability in levocetirizine pharmacometrics among individuals, a crucial aspect for establishing its clinical use. The gender differences in pharmacokinetics and the extent of variation in pharmacodynamics have not been definitively identified. The primary goal of this study was to investigate gender differences in levocetirizine pharmacokinetics and quantitatively predict and compare how these gender-related pharmacokinetic differences impact pharmacodynamics, using population pharmacokinetic-pharmacodynamic modeling. Bioequivalence results for levocetirizine (only from the control formulation) were obtained from both healthy Korean men and women. Physiological and biochemical parameters for each individual were utilized as pharmacokinetic comparison and modeling data between genders. Pharmacodynamic modeling was performed using reported data on antihistamine responses following levocetirizine exposure. Gender, weight, body surface area, peripheral distribution volume, albumin, central-peripheral inter-compartmental clearance, and the fifth sequential absorption rate constant were explored as effective covariates. A comparison of the model simulation results showed a higher maximum concentration and faster plasma loss in females than in males, resulting in a faster recovery to baseline of the antihistamine effect; however, the absolute differences between genders in the mean values were not large within 10 ng/mL (for plasma concentrations) or % (wheal and flare size changes). Regarding the pharmacokinetics and pharmacodynamics of levocetirizine, the gender effect may not be significant when applying the usual dosage (5 mg/day). This study will be useful for bridging the knowledge gap in scientific precision medicine by introducing previously unconfirmed information regarding gender differences in levocetirizine pharmacometrics.
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This study investigated the preventive effects of whey protein fermented with Lactobacillus gasseri IM13 (F-WP) against dexamethasone (DEX)-induced muscle atrophy. C2C12 muscle cells were treated with F-WP followed by DEX treatment. Dexamethasone treatment inhibited myotube formation and the expression of myogenic regulatory factors; however, pretreatment with F-WP attenuated DEX-induced damage. The F-WP significantly activated the phosphorylation of the IGF-1/PI3K/AKT pathway and improved muscle homeostasis suppressed by DEX. Moreover, F-WP alleviated the phosphorylation of mTOR, S6K1, and 4E-BP1 and enhanced muscle protein synthesis. Muscle-specific ubiquitin ligases and autophagy lysosomes, which were activated by the dephosphorylation of FOXO3a by DEX treatment, were significantly attenuated by F-WP pretreatment of myotubes. For peptidomic analysis, F-WP was fractionated using preparative HPLC (prep-HPLC), and the AA sequences of 11 peptides were identified using MALDI-TOF/MS/MS. In conclusion, fermentation of whey protein by the specific probiotic strain IM13 produced bioactive peptides with high antioxidant and anti-sarcopenic-sarcopenic effects, which markedly enhanced myogenesis and muscle protein synthesis while diminishing muscle protein degradation compared with intact whey protein.
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This study aimed to quantify and explain inter-subject variability in morniflumate pharmacokinetics and identify effective covariates through population pharmacokinetics modeling. Models were constructed using bioequivalence pharmacokinetics results from healthy Korean males and individual physiological and biochemical parameters. Additionally, we incorporated previously reported pharmacokinetics results of niflumic acid, a major active metabolite of morniflumate, to extend the established population pharmacokinetics model and predict niflumic acid pharmacokinetics. Moreover, we used quantitative reports of leukotriene B4 (LTB4) synthesis inhibition in response to niflumic acid exposure to predict drug efficacy using Sigmoid Emax model. Population pharmacokinetics profiles of morniflumate were described using a multi-absorption (5-sequential) two-compartment model, and analysis of inter-individual variability suggested that volume of distribution in peripheral compartment was correlated with body mass index (BMI). Model simulation results showed that individuals with lower BMI had higher plasma concentrations of morniflumate and niflumic acid, resulting in increased and sustained inhibition of LTB4 synthesis. Under steady-state conditions, average plasma concentrations of morniflumate and niflumic acid were 2.66-2.68 times higher in group with a BMI of 17.36 kg/m2 compared to the group with a BMI of 28.41 kg/m2. Additionally, inhibition of LTB4 synthesis was 1.02 times higher in group with a BMI of 17.36 kg/m2 compared to group with a BMI of 28.41 kg/m2, and the fluctuation was significantly reduced from 6.06 to 0.01%. These findings suggest that the concentration of active metabolite in plasma following morniflumate exposure was lower in the obese group compared to the normal group, thus potentially reducing the drug's efficacy.
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Antiinflamatorios no Esteroideos , Ácido Niflúmico , Masculino , Humanos , Ácido Niflúmico/farmacocinética , Leucotrieno B4 , República de CoreaRESUMEN
Levodropropizine, a nonopioid antitussive agent, is being increasingly used in clinical practice with the development of several formulations for symptomatic relief of acute and chronic bronchitis. However, scientific and quantitative population pharmacokinetic analyses of levodropropizine are lacking. Moreover, no integrated quantitative comparison has been performed between formulations. This study quantitatively evaluated and predicted pharmacokinetic properties of formulations through population pharmacokinetic model-based comparisons of commercially available formulations. Plasma concentration profile results from bioequivalence studies of 60-mg immediate release (IR) levodropropizine tablets in 40 healthy Korean males were used as population pharmacokinetic modeling data. For interindividual variability in levodropropizine pharmacokinetics, body surface area was identified as an effective covariate that was positively correlated with peripheral compartment distribution volume. Population pharmacokinetic model for IR tablets well-described the levodropropizine syrup and capsule datasets, suggesting no significant differences in pharmacokinetics among IR tablets, syrups, and capsules of levodropropizine. In contrast, pharmacokinetic profiles differed between 90-mg controlled release (CR) and IR levodropropizine tablets; however, separate parameter estimation was possible by applying the same model structure. In terms of pharmacokinetics, twice-daily regimen of 90-mg CR tablets was equivalent to thrice-daily regimen of 60-mg IR tablets. However, at steady-state, interindividual plasma concentration variability within population was reduced by approximately 36.71-83.18%. For levodropropizine CR tablets, a high-fat diet significantly delayed gastrointestinal absorption but maintained overall plasma exposure equivalent. This study provides useful quantitative judgment data for precision medicine of levodropropizine and can be helpful in predicting the pharmacokinetics of levodropropizine based on commercialized formulation switching.
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Modelos Biológicos , Comprimidos , Masculino , Humanos , Adulto , Adulto Joven , Equivalencia Terapéutica , Antitusígenos/farmacocinética , Antitusígenos/administración & dosificación , Antitusígenos/sangre , Preparaciones de Acción Retardada , Dieta , Estudios Cruzados , Interacciones Alimento-Droga , Cápsulas , Glicoles de PropilenoRESUMEN
Rabeprazole is a proton pump inhibitor that inhibits gastric acid production and increases gastric pH; it is widely used clinically as a treatment option for gastritis and gastric ulcers. However, information on the inter-individual variability of rabeprazole pharmacometrics, which is a key element in establishing its scientific clinical use, is still lacking. Particularly, the differences in pharmacokinetics between genders and the degree of variation in pharmacodynamics have not been clearly identified. Thus, the main purpose of this study was to explore any differences in rabeprazole pharmacokinetics between genders and to quantitatively predict and compare the effects of any differences in pharmacokinetics between genders on known pharmacodynamics using population pharmacokinetic-pharmacodynamic modeling. To compare pharmacokinetics and modeling data between genders, bioequivalence results were used simultaneously on healthy Korean men and women using the physiological and biochemical parameters derived from each individual. Pharmacodynamic modeling was performed based on the data of previously reported gastric pH changes in response to rabeprazole plasma concentrations, which was co-linked to the central compartmental bioavailable concentration in the population pharmacokinetic model. There was no significant difference in the level of rabeprazole exposure and elimination of plasma between genders following oral administration of 10 mg enteric-coated rabeprazole tablets; however, there was a clear delay in absorption in women compared to men. Additionally, a comparison of pharmacokinetic parameters normalized to body weight between genders showed that the maximum plasma concentrations were significantly higher in women than in men, again suggesting gender differences in rabeprazole absorption. The population pharmacokinetic profiles for rabeprazole were described using a three-sequential multi-absorption with lag time (Tlag) two-compartment model, whereas body surface area and gender were explored as effective covariates for absorption rate constant and Tlag, respectively. The effect of increased gastric pH due to plasma exposure to rabeprazole was explained using the Sigmoid Emax model, with the baseline as a direct response. The significantly longer rabeprazole Tlag in females delayed the onset of an effect by an average of 1.58 times (2.02-3.20 h), yet the overall and maximum effects did not cause a significant difference within 15%. In the relative comparison of the overall efficacy of rabeprazole enteric-coated tablet administration between genders, it was predicted based on the model that males would have higher efficacy. This study will be very useful in broadening the perspective of interpreting drug diversity between individuals and narrowing the gap in knowledge related to scientific precision medicine by presenting new information on gender differences in rabeprazole pharmacometrics that had not been previously identified.
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P-glycoprotein (P-gp) is a widely membrane-expressed multi-drug transporter. It is unclear whether the pharmacokinetic diversity of P-gp substrates is highly dependent on ABCB1 polymorphisms encoding P-gp. The purpose of this study is to analyze the mechanistic function of P-gp through in silico molecular modeling and to approach the resolution of controversy over pharmacokinetic differences according to ABCB1 polymorphisms. P-gp conformations of apo, ligand-docked, and outward-facing states can be modeled based on structural information of human P-gp. And polymorphic P-gp structures were constructed through homology modeling. ABCB1 c.2677G > T/A (Ala893Ser/Thr), did not correspond to P-gp's nucleotide-binding-domain (NBD) or drug-binding-pocket (DBP) or involve mechanical conformational changes. Although amino acid substitution by ABCB1 c.2677G > T/A caused a 30 % increased strain in an α-helix hinge between the NBD and DBP in P-gp's internal tunnel, there were no overall structural changes compared to wild-type. ABCB1 c.2677G > T/A may increase torsional energy, impacting conformational change rate, but this does not significantly affect P-gp's general functioning. Fexofenadine docking into P-gp's DBP explained the substrate interaction, but no effect by ABCB1 c.2677G > T/A was confirmed. Our findings provide additional insights useful in resolving the debate about the influence of ABCB1 polymorphisms on the interindividual pharmacokinetic variability of P-gp substrates.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Proteínas de Transporte de Membrana , Humanos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Simulación por Computador , Polimorfismo GenéticoRESUMEN
Age-related changes and interindividual variability in the degree of exposure to hazardous substances in the environment are pertinent factors to be considered in human risk assessment. Existing risk assessments remain in a one-size-fits-all approach, often without due consideration of inter-individual toxicokinetic variability factors, such as age. The purpose of this study was to advance from the existing risk assessment of hazardous substances based on toxicokinetics to a precise human risk assessment by additionally considering the effects of physiologic and metabolic fluctuations and interindividual variability in age. Qualitative age-associated physiologic and metabolic changes in humans, obtained through a meta-analysis, were quantitatively modeled to produce the final biological age algorithm (BAA). The developed BAAs (for males) were extended and applied to the reported testicular reproductive toxicity-focused di-isobutyl-phthalate (DiBP)-mono-isobutyl-phthalate (MiBP) physiologically based toxicokinetic (PBTK) model in males. The advanced PBTK model combined with the BAA was applied to the human risk assessment based on MiBP biomonitoring data. As a result, the specialized DiBP external exposure values for each age could be estimated. Additionally, by applying the Monte Carlo simulation, the distribution of internal exposure diversity among individuals according to the same external exposure dose could be estimated. The contributions of physiologic and metabolic factors to the age-dependent toxicokinetic changes were approximately 93.41-99.99 and 0.01-6.59%, respectively. In addition, the relative contribution of metabolic factors was major in infants and continued to decrease as age increased (up to about age 30 years). This study provides a step-by-step platform that can be widely applied to overcome the limitations of existing toxicokinetic models that still require interindividual pharmacokinetic variability explanations. This will be important for the rationalization and explanation of inter-individual variability in the pharmacokinetics of many substances.
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Sustancias Peligrosas , Modelos Biológicos , Masculino , Lactante , Humanos , Adulto , Toxicocinética , Medición de Riesgo , EnvejecimientoRESUMEN
Fexofenadine is useful in various allergic disease treatment. However, the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking. This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmacokinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability. Polymorphisms of the organic-anion-transporting-polypeptide (OATP) 1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity. Therefore, modeling was performed using fexofenadine oral exposure data according to the OATP1B1- and 2B1-polymorphisms. OATP1B1 and 2B1 were identified as effective covariates of clearance (CL/F) and distribution volume (V/F)-CL/F, respectively, in fexofenadine pharmacokinetic variability. CL/F and average steady-state plasma concentration of fexofenadine differed by up to 2.17- and 2.20-folds, respectively, depending on the OATP1B1 polymorphism. Among the individuals with different OATP2B1 polymorphisms, the CL/F and V/F differed by up to 1.73- and 2.00-folds, respectively. Ratio of the areas under the curves following single- and multiple-administrations, and the cumulative ratio were significantly different between OATP1B1- and 2B1-polymorphism groups. Based on quantitative prediction comparison through a model-based approach, OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability. Based on the established pharmacokinetic-pharmacodynamic relationship, the difference in fexofenadine efficacy according to genetic polymorphisms of OATP1B1 and 2B1 was 1.25- and 0.87-times, respectively, and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well. This population pharmacometrics study will be a very useful starting point for fexofenadine precision medicine.
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This study aimed to evaluate the cholesterol-lowering and antioxidant activities of soymilk fermented with probiotic Lactobacillaceae strains and to investigate the production of related bioactive compounds. Lactiplantibacillus plantarum KML06 (KML06) was selected for the fermentation of soymilk because it has the highest antioxidant, cholesterol-lowering, and ß-glucosidase activities among the 10 Lactobacillaceae strains isolated from kimchi. The genomic information of strain KML06 was analyzed. Moreover, soymilk fermented with KML06 was evaluated for growth kinetics, metabolism, and functional characteristics during the fermentation period. The number of viable cells, which was similar to the results of radical scavenging activities and cholesterol assimilation, as well as the amount of soy isoflavone aglycones, daidzein, and genistein, was the highest at 12 h of fermentation. These results indicate that soymilk fermented with KML06 can prevent oxidative stress and cholesterol-related problems through the production of soy isoflavone aglycones.
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Isoflavonas , Leche de Soja , Antioxidantes/metabolismo , Fermentación , beta-Glucosidasa/metabolismo , Microbiología de Alimentos , Isoflavonas/metabolismo , Lactobacillus/metabolismo , Leche de Soja/metabolismoRESUMEN
Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to explore dosage regimens. The bioequivalence results of healthy Korean males, biochemical analysis, and CYP2C9 genotyping information were utilized in modeling. The established model has been sufficiently verified through a bootstrap, goodness-of-fit, visual predictive check, and normalized prediction distribution error. External data sets derived from the literature were used for further model validation. The final model could be used to verify the dosage regimen through multiple exposure simulations according to the numerical change of the selected covariates. Zaltoprofen pharmacokinetics could be explained by a two-compartment with a first-order absorption model. Creatinine clearance (CrCL) and albumin were identified as effective covariates related to interindividual zaltoprofen pharmacokinetic variability, and they had positive and negative correlations with clearance (CL/F), respectively. The differences in pharmacokinetics between individuals according to CYP2C9 genetic polymorphisms (*1/*1 and *1/*3) were not significant or valid covariates. The model simulation confirmed that zaltoprofen pharmacokinetics could significantly differ as the CrCL and albumin levels changed within the normal range. Steady-state plasma exposure to zaltoprofen was significantly reduced in the group with CrCL and albumin levels of 130 mL/min and 3.5 g/dL, respectively, suggesting that dose adjustment may be necessary. This study is useful to guide precision medicine of zaltoprofen and provides scientific quantitative judgment data for its clinical applications.
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BACKGROUND: Meloxicam, used for treating inflammatory diseases, shows large differences in metabolism according to CYP2C9 genetic polymorphisms; however, there are few studies on dose regimen setting based on quantitative predictions. OBJECTIVE: The aim of this study was to determine the appropriate meloxicam dose regimen for each genotype through population pharmacokinetic-pharmacodynamic modeling of meloxicam by considering CYP2C9 genetic polymorphisms. METHODS: For modeling, previously reported pharmacokinetic (plasma concentration)-pharmacodynamic (inhibition of thromboxane B2 generation) data of meloxicam were collected for CYP2C9 genetic polymorphisms (n = 43). And these data were mainly used in the modeling process. Through simulations of the established models, steady-state pharmacokinetic-pharmacodynamic profiles were obtained according to meloxicam multiple exposures for each CYP2C9 genotype, and predictions were made based on dose regimen changes. RESULTS: Genetic polymorphisms of CYP2C9 were identified as key covariates that significantly affected pharmacokinetic variability of meloxicam between individuals. The developed meloxicam population pharmacokinetic-pharmacodynamic model predicted pharmacokinetic results of the 7.5 mg meloxicam administration groups (n = 26) for CYP2C9*1/*1 and *1/*3 as an external validation. The results of model simulation revealed that the differences were 2.39-5.42 times for steady-state mean plasma concentrations and 1.21-1.71 times for the degree of inhibition of thromboxane B2 generation following multiple exposures for CYP2C9*1/*1 versus *1/*13, *1/*3, and *3/*3. This suggested that thromboxane B2 inhibition following increased plasma exposure to meloxicam differed significantly according to CYP2C9 genetic polymorphisms. The dose of meloxicam in CYP2C9*1/*13, *1/*3, and *3/*3 was randomly adjusted to 1.6-15 mg to approximate the mean thromboxane B2 inhibition for CYP2C9*1/*1 at steady state, the dose intervals varied from 24 h to 48 h. CONCLUSIONS: The results suggested that clinical dose adjustment of meloxicam would be necessary to account for CYP2C9 genetic polymorphisms and reduce side effects. This study suggests a clearer direction for setting up clinical therapy based on personalized medicine and quantitative predictions for meloxicam.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Humanos , Meloxicam , Citocromo P-450 CYP2C9/genética , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Polimorfismo Genético , Genotipo , TromboxanosRESUMEN
Background: Cranial nerve-related diseases such as brain tumors, Alzheimer's disease, and epilepsy are serious diseases that continue to threaten human. Brain-related diseases are increasing worldwide, including in the United States and Korea, and these increases are closely related to the exposure to harmful substances and excessive stress caused by rapid industrialization and environmental pollution. Drug delivery to the brain is very important for the effective prevention and treatment of brain-related diseases. However, due to the presence of the blood-brain barrier and the extensive first-pass metabolism effect, the general routes of administration such as oral and intravenous routes have limitations in drug delivery to the brain. Therefore, as an alternative, the nasal-brain drug delivery route is attracting attention as a route for effective drug delivery to the brain. Areas covered: This review includes physiological factors, advantages, limitations, current application status, especially in clinical applications, and the necessary factors for consideration in formulation development related to nasal-brain drug delivery. Expert opinion: The nasal-brain drug delivery route has the advantage of enhancing drug delivery to the brain locally, mainly through the olfactory route rather than the systemic circulation. The nasal-brain lymphatic system has recently attracted attention, and it has been implied that the delivery of anticancer drugs to the brain nervous system is possible effectively. However, there are limitations such as low drug permeability, as well as nasal mucosa and the mucociliary system, as obstacles in nasal-brain drug delivery. Therefore, to overcome the limitations of nasal-brain drug delivery, the use of nanocarriers and mucoadhesive agents is being attempted. However, very few drugs have been officially approved for clinical application via the nasal-brain drug delivery route. This is probably because the understanding of and related studies on nasal-brain drug delivery are limited. In this review, we tried to explore the major considerations and target factors in drug delivery through the nasal-brain route based on physiological knowledge and formulation research information. This will help to provide a mechanistic understanding of drug delivery through the nasal-brain route and bring us one step closer to developing effective formulations and drugs in consideration of the key factors for nasal-brain drug delivery.