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Biomedicine & Pharmacotherapy =... Jul 2022Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to...
Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling.
Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to its diverse pharmacological activities. Although there have been several preclinical and clinical investigations of resveratrol, the contributions of gut phase-II metabolism and enterohepatic circulation to the oral bioavailability and pharmacokinetics of resveratrol remain unclear. Furthermore, a physiologically-based pharmacokinetic (PBPK) model that accurately describes and predicts the systemic exposure profiles of resveratrol in clinical settings has not been developed. Experimental data were acquired from several perspectives, including in vitro protein binding and blood distribution, in vitro tissue S9 metabolism, in situ intestinal perfusion, and in vivo pharmacokinetics and excretion studies. Using these datasets, an in-house whole-body PBPK model incorporating route-dependent phase-II (glucuronidation and sulfation) gut metabolism and enterohepatic circulation processes was constructed and optimized for chemical-specific parameters. The developed PBPK model aligned with the observed systemic exposure profiles of resveratrol in single and multiple dosing regimens with an acceptable accuracy of 0.538-0.999-fold errors. Furthermore, the model simulations elucidated the substantial contribution of gut first-pass metabolism to the oral bioavailability of resveratrol and suggested differential effects of enterohepatic circulation on the systemic exposure of resveratrol between rats and humans. After partial modification and verification, our proposed PBPK model would be valuable to optimize dosage regimens and predict food-drug interactions with resveratrol-based natural products in various clinical scenarios.
Topics: Animals; Biological Availability; Enterohepatic Circulation; Humans; Inactivation, Metabolic; Models, Biological; Rats; Resveratrol
PubMed: 35609369
DOI: 10.1016/j.biopha.2022.113141 -
Anesthesiology Feb 2004Intrathecal administration of antisense oligonucleotides is a frequently used technique to alter gene expression for research purposes. However, in the future, antisense...
BACKGROUND
Intrathecal administration of antisense oligonucleotides is a frequently used technique to alter gene expression for research purposes. However, in the future, antisense oligonucleotides will likely be administered intrathecally to humans for therapeutic purposes. To date, there have been no systematic studies of the pharmacokinetics of intrathecal oligonucleotides. This study was designed to fill that knowledge gap.
METHODS
Microdialysis probes were placed intrathecally at the L4, L1, and T11 vertebral levels and epidurally at the L4 vertebral level in pigs. One of the study oligodeoxynucleotides (10-, 18-, or 30-nucleotide-long sequences of the human MDR-1 gene) was injected intrathecally at the L4 level at time 0. Microdialysis samples were obtained for measurement of oligodeoxynucleotide samples at 5-min intervals until 20 min, 10-min intervals until 60 min, and 20-min intervals until 180 min. Noncompartmental pharmacokinetic analysis was performed using PK Solutions software.
RESULTS
Mean residence time and terminal elimination half-life did not differ significantly among the three oligodeoxynucleotides at any sampling site. In contrast, area under the concentration-time curve differed significantly among the oligodeoxynucleotides at all sampling sites and was inversely related to oligodeoxynucleotide length at the L4 and L1 intrathecal sites but not the T11 or epidural sampling sites. Similarly, clearance and volumes of distribution at the L4 level differed significantly among the oligodeoxynucleotides and were directly related to oligodeoxynucleotide length.
CONCLUSION
The intrathecal pharmacokinetics of oligodeoxynucleotides are largely determined by oligodeoxynucleotide length. This contrasts with smaller drug molecules, such as opioids, for which intrathecal and epidural pharmacokinetics are largely determined by lipid solubility, not size. The potential clinical utility of this information is that oligodeoxynucleotide distribution within the central nervous system may be controllable to some degree by varying oligodeoxynucleotide length.
Topics: Animals; Area Under Curve; Autoradiography; Female; Half-Life; Injections, Spinal; Male; Metabolic Clearance Rate; Microdialysis; Oligonucleotides; Swine
PubMed: 14739806
DOI: 10.1097/00000542-200402000-00021 -
Drug Discovery Today Sep 2020Over the past two decades, an in silico absorption, distribution, metabolism, and excretion (ADMET) platform has been created at Bayer Pharma with the goal to generate... (Review)
Review
Over the past two decades, an in silico absorption, distribution, metabolism, and excretion (ADMET) platform has been created at Bayer Pharma with the goal to generate models for a variety of pharmacokinetic and physicochemical endpoints in early drug discovery. These tools are accessible to all scientists within the company and can be a useful in assisting with the selection and design of novel leads, as well as the process of lead optimization. Here. we discuss the development of machine-learning (ML) approaches with special emphasis on data, descriptors, and algorithms. We show that high company internal data quality and tailored descriptors, as well as a thorough understanding of the experimental endpoints, are essential to the utility of our models. We discuss the recent impact of deep neural networks and show selected application examples.
Topics: Animals; Computer Simulation; Humans; Intestinal Absorption; Machine Learning; Models, Theoretical; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 32652309
DOI: 10.1016/j.drudis.2020.07.001 -
British Journal of Pharmacology Dec 2009Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose... (Comparative Study)
Comparative Study
BACKGROUND AND PURPOSE
Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations.
EXPERIMENTAL APPROACH
The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg kg(-1) min(-1)) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling.
KEY RESULTS
Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC(last) and AUC(inf) between both formulations were acceptable for bioequivalence, whereas that of C(max) was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E(0) (baseline ApEn)-E(max) (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V(1) of both formulations and sex for k(21) of microemulsion propofol. The blood-brain equilibration rate constants (k(e0), min(-1)) were 0.476 and 0.696 for microemulsion and LCT propofol respectively.
CONCLUSIONS AND IMPLICATIONS
Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.
Topics: Anesthetics, Intravenous; Animals; Area Under Curve; Body Weight; Cross-Over Studies; Dogs; Dose-Response Relationship, Drug; Electroencephalography; Emulsions; Entropy; Female; Male; Models, Biological; Nonlinear Dynamics; Propofol; Random Allocation; Therapeutic Equivalency; Tissue Distribution; Triglycerides
PubMed: 19925493
DOI: 10.1111/j.1476-5381.2009.00509.x -
British Journal of Clinical Pharmacology May 2019Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and...
AIMS
Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects.
METHODS
Plasma concentration-time data of agomelatine and its metabolites were collected from a 4-period, cross-over bioequivalence study, in which 44 healthy subjects received 25 mg agomelatine tablets orally. Nonlinear mixed effects modelling was used to characterize the pharmacokinetics and variability of agomelatine and its metabolites. Deterministic simulations were carried out to investigate the influence of pathological changes due to liver disease on agomelatine pharmacokinetics.
RESULTS
A semiphysiological pharmacokinetic model with parallel first-order absorption and a well-stirred liver compartment adequately described the data. The estimated IIV and interoccasion variability of the intrinsic clearance of agomelatine were 130.8% and 28.5%, respectively. The IIV of the intrinsic clearance turned out to be the main cause of the variability of area under the curve-based agomelatine exposure. Simulations demonstrated that a reduction in intrinsic clearance or liver blood flow, and an increase in free drug fraction had a rather modest influence on agomelatine exposures (range: -50 to 200%). Portosystemic shunting, however, substantially elevated agomelatine exposure by 12.6-109.1-fold.
CONCLUSIONS
A semiphysiological pharmacokinetic model incorporating first-pass hepatic extraction was developed for agomelatine and its main metabolites. The portosystemic shunting associated with liver disease might lead to significant alterations of agomelatine pharmacokinetics, and lead to substantially increased exposure.
Topics: Acetamides; Administration, Oral; Antidepressive Agents; Area Under Curve; Asian People; Biological Variation, Population; Cross-Over Studies; Depressive Disorder, Major; Female; Healthy Volunteers; Humans; Liver; Liver Function Tests; Male; Metabolic Clearance Rate; Models, Biological; Tablets; Therapeutic Equivalency; Young Adult
PubMed: 30761579
DOI: 10.1111/bcp.13902 -
Veterinary Anaesthesia and Analgesia Jul 2022To investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).
OBJECTIVE
To investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).
STUDY DESIGN
A crossover design with an 11 day washout period.
ANIMALS
A total of eight young male reindeer, aged 1.5-2.5 years and weighing 74.3 ± 6.3 kg, mean ± standard deviation.
METHODS
The reindeer were administered meloxicam (0.5 mg kg IV or orally). Blood samples were repeatedly collected from the jugular vein for up to 72 hours post administration. Plasma samples were analysed for meloxicam concentrations with ultraperformance liquid chromatography combined with triple quadrupole mass spectrometry. Noncompartmental analysis for determination of pharmacokinetic variables was performed.
RESULTS
The pharmacokinetic values, median (range), were determined. Elimination half-life (t) with the IV route (n = 4) was 15.2 (13.2-16.8) hours, the volume of distribution at steady state was 133 (113-151) mL kg and clearance was 3.98 (2.63-5.29) mL hour kg. After oral administration (n = 7), the peak plasma concentration (C) was detected at 6 hours, t was 19.3 (16.7-20.5) hours, C 1.82 (1.17-2.78) μg mL and bioavailability (n = 3) 49 (46-73)%. No evident adverse effects were detected after either administration route.
CONCLUSIONS AND CLINICAL RELEVANCE
A single dose of meloxicam (0.5 mg kg IV or orally) has the potential to maintain the therapeutic concentration determined in other species for up to 3 days in reindeer plasma.
Topics: Administration, Oral; Animals; Area Under Curve; Biological Availability; Half-Life; Male; Meloxicam; Reindeer
PubMed: 35659721
DOI: 10.1016/j.vaa.2022.04.005 -
The AAPS Journal Oct 2005In a seminal article on population pharmacokinetic modeling, researchers demonstrated how means and variances of pharmacokinetic parameters for a patient population... (Review)
Review
In a seminal article on population pharmacokinetic modeling, researchers demonstrated how means and variances of pharmacokinetic parameters for a patient population could be inferred from sparse data collected under conditions of routine patient care. But they also identified 4 potential concerns about their methodology: unobserved confounding variables may bias the inferences; conditions under which data are collected may lead to inaccuracies of reporting or recording; correlations among important predictor variables may reduce statistical efficiency; and costs cannot be controlled by principles of study design. Experiences are reviewed that relate to these potential disadvantages. A method is presented for diagnosing the possible presence of confounding. A model is constructed and applied that captures the influences of data inaccuracies. An example of selecting from among correlated covariates is summarized. Finally, a methodology for optimal study design is reviewed and applied to an example.
Topics: Animals; Humans; Models, Biological; Pharmacokinetics; Time Factors
PubMed: 16353917
DOI: 10.1208/aapsj070238 -
Computers in Biology and Medicine Dec 2023We present a novel Pharmacokinetic/Pharmacodynamic (PK/PD) model for the induction phase of anesthesia, incorporating the ψ-Caputo fractional derivative. By employing...
We present a novel Pharmacokinetic/Pharmacodynamic (PK/PD) model for the induction phase of anesthesia, incorporating the ψ-Caputo fractional derivative. By employing the Picard iterative process, we derive a solution for a nonhomogeneous ψ-Caputo fractional system to characterize the dynamical behavior of the drugs distribution within a patient's body during the anesthesia process. To explore the dynamics of the fractional anesthesia model, we perform numerical analysis on solutions involving various functions of ψ and fractional orders. All numerical simulations are conducted using the MATLAB computing environment. Our results suggest that the ψ functions and the fractional order of differentiation have an important role in the modeling of individual-specific characteristics, taking into account the complex interplay between drug concentration and its effect on the human body. This innovative model serves to advance the understanding of personalized drug responses during anesthesia, paving the way for more precise and tailored approaches to anesthetic drug administration.
Topics: Humans; Anesthesia; Pharmacokinetics; Computer Simulation
PubMed: 37976826
DOI: 10.1016/j.compbiomed.2023.107679 -
Yakugaku Zasshi : Journal of the... 2019In this review, 9 compounds with insufficient absorption characteristics, safety or efficacy were selected from among the compounds for which the author was in charge of... (Review)
Review
In this review, 9 compounds with insufficient absorption characteristics, safety or efficacy were selected from among the compounds for which the author was in charge of development between 2000 and 2005, in order to evaluate the pharmacokinetic (PK) approaches used to develop these compounds. Optimization of the PK characteristics of a compound at the early stage of chemical design was found to be the most important factor for successful development. For example, (i) selecting class I or II drugs in the biopharmaceutical classification system, while avoiding efflux transporters, and introducing an appropriate dissociation moiety into a compound to make it soluble lead to sufficient drug absorption; (ii) designing compounds whose production of reactive metabolites, such as acyl glucuronide, does not largely affect total metabolism, yet helps to prevent abnormal PK caused by reactive metabolites. Other factors include (i) selection of a drug efficacy evaluation system based on the correct understanding of the relationship between PK and pharmacodynamics (PD) helps to solve species differences in PD; (ii) the establishment of a nonclinical study based on the identification of the involvement of specific cytochrome P450 molecules in the total metabolic clearance of a drug (fs) helps to solve species differences in PK; and (iii) PK analysis using the tube model for hepatic extraction kinetics, and knowledge of the fs of the victim drug, lead to successful drug-drug interaction (DDI) prediction. I hope that this review aids in future drug discovery or development.
Topics: Cytochrome P-450 Enzyme System; Drug Design; Drug Discovery; Drug Interactions; Humans; Metabolic Clearance Rate; Models, Biological; Pharmacokinetics
PubMed: 30828023
DOI: 10.1248/yakushi.18-00190 -
PloS One 2020The aim of the study was to determine the various pharmacokinetic parameters of the newly developed cost-effective aceclofenac 100 mg tablet formulation (F-15) and to...
The aim of the study was to determine the various pharmacokinetic parameters of the newly developed cost-effective aceclofenac 100 mg tablet formulation (F-15) and to establish the bioequivalence against the marketed brand (ACEMED). Both products (test and reference) were given to 12 healthy non-smokers male subjects with overnight fasting of >10hr. The study was a randomized, single-dose, open-label, two sequence, and two treatment crossover design, with a washout period of 2 weeks. Blood samples (5 mL) from the human subjects were collected before (0 hr) and after drug administration at 13different time points (0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12 and 18 hrs). The drug plasma concentration was analyzed by a validated RP-HPLC method using a solvent system containing acetonitrile and deionized water (60:40% v/v). Linearity was found to be 0.999 over the drug concentration range of 50μg/mL to 0.05μg/mL with LLOQ and LOD of 0.05μg/mL and 0.025μg/mL respectively. Non-compartmental pharmacokinetic analysis was performed using Kinetica® (ver. 5.1) software. Using the log-transformed data Cmax, AUC0-t, AUC0-∞, AUMCtot, and MRT were calculated. The Cmax of the test and brand was found to be 8.629±1.251μg/mL and 8.478±0.913μg/mL. The AUC0-t and AUC0-∞ of the test and the reference were computed to be 20.890 ±2.2021μg/mL.h, 23.272 ±1.914 μg/mL.h and 19.850 ±2.911 μg/mL.h, 22.890 ± 2.110 μg/mL.h correspondingly. Two-way analysis of variance (ANOVA) test and two one-sided t-test (p>0.05; non-significant) were applied to assess the variation in the period, sequence, subjects, and treatment. Geometric mean ratios for above mentioned pharmacokinetic parameters of reference/test were found within the acceptable FDA limits of 80-125% using 90% CI. There was no inter and intrasubject variation (p> 0.05) that was observed. Therefore, the directly compressible aceclofenac (100 mg) test formulation and the commercial reference tablets were declared to be biosimilar.
Topics: Adult; Analysis of Variance; Area Under Curve; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Cross-Over Studies; Diclofenac; Healthy Volunteers; Humans; Male; Tablets; Therapeutic Equivalency
PubMed: 32898192
DOI: 10.1371/journal.pone.0238951