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Basic & Clinical Pharmacology &... Apr 2021Activated charcoal both reduces primary drug absorption and enhances drug elimination. However, the two mechanisms of action overlap and are indistinguishable from each... (Meta-Analysis)
Meta-Analysis Review
Activated charcoal both reduces primary drug absorption and enhances drug elimination. However, the two mechanisms of action overlap and are indistinguishable from each other. In order to estimate the extend of enhanced elimination, we summarized the effect of activated charcoal on intravenously administered drugs, where reduced drug exposure can be attributed to enhanced elimination. We performed a meta-analysis of randomized controlled studies evaluating the effect of orally administered activated charcoal on the systemic exposure of intravenously administered drugs. We searched the bibliographic databases PubMed, Embase and Cochrane. Meta-regression analyses of selected physiochemical drug properties on the effect sizes of activated charcoal were performed. All but one of 21 included studies used multiple-dose activated charcoal (MDAC). MDAC reduced the median half-life of the intravenously administered study drugs by 45.7% (interquartile range: 15.3%-51.3%) and area under the concentration time curve by 47.0% (interquartile range: 36.4%-50.2%). MDAC significantly improved drug elimination across nine different intravenously administered drugs, but we were unable to identify factors allowing extrapolation to other drugs. The results offer a possible and plausible rationale for the previously observed effects of single-dose activated charcoal beyond the timeframe where ingested drug is present in the gastro-intestinal tract.
Topics: Administration, Intravenous; Administration, Oral; Area Under Curve; Charcoal; Drug Interactions; Gastrointestinal Absorption; Half-Life; Humans; Metabolic Clearance Rate; Randomized Controlled Trials as Topic
PubMed: 33386684
DOI: 10.1111/bcpt.13553 -
Critical Care Clinics Apr 2008For appropriate antibiotic therapy and selection, the clinician must be familiar with pharmacodynamic concepts that integrate an antibiotic's microbiologic activity,... (Review)
Review
For appropriate antibiotic therapy and selection, the clinician must be familiar with pharmacodynamic concepts that integrate an antibiotic's microbiologic activity, pharmacokinetic properties, and mode of bacterial killing. Much of the traditional dosing methods that continue to this day are based more on habit rather than science. This article addresses these issues and explains the basis for the new scientific ways to administer antibiotics to optimize patient outcomes.
Topics: Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Biological Availability; Critical Care; Half-Life; Humans; Tissue Distribution
PubMed: 18361949
DOI: 10.1016/j.ccc.2007.12.008 -
Journal of Medicinal Chemistry Jul 2023We developed a novel drug metabolism and pharmacokinetics (DMPK) analysis platform named DruMAP. This platform consists of a database for DMPK parameters and programs...
We developed a novel drug metabolism and pharmacokinetics (DMPK) analysis platform named DruMAP. This platform consists of a database for DMPK parameters and programs that can predict many DMPK parameters based on the chemical structure of a compound. The DruMAP database includes curated DMPK parameters from public sources and in-house experimental data obtained under standardized conditions; it also stores predicted DMPK parameters produced by our prediction programs. Users can predict several DMPK parameters simultaneously for novel compounds not found in the database. Furthermore, the highly flexible search system enables users to search for compounds as they desire. The current version of DruMAP comprises more than 30,000 chemical compounds, about 40,000 activity values (collected from public databases and in-house data), and about 600,000 predicted values. Our platform provides a simple tool for searching and predicting DMPK parameters and is expected to contribute to the acceleration of new drug development. DruMAP can be freely accessed at: https://drumap.nibiohn.go.jp/.
Topics: Drug Development; Pharmacokinetics
PubMed: 37449459
DOI: 10.1021/acs.jmedchem.3c00481 -
Clinical and Translational Science May 2017
Review
Topics: Animals; Dose-Response Relationship, Drug; Humans; Membrane Transport Proteins; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 28160433
DOI: 10.1111/cts.12448 -
European Journal of Pharmaceutical... Jan 2022The purpose of the present study was to investigate the suitability of equilibrium slurry pH (pH) as a surrogate of solid surface pH during drug dissolution (pH). A...
The purpose of the present study was to investigate the suitability of equilibrium slurry pH (pH) as a surrogate of solid surface pH during drug dissolution (pH). A comprehensive calculation scheme for pH and pH was formalized based on the principle of charge neutrality (equilibrium charge neutrality for pH and charge flux neutrality for pH). The formalized scheme was then used to investigate the validity of pH ≈ pH approximation. The approximation of pH ≈ pH was suggested to be accurate for small molecules (ca. MW = 150) in high concentration buffer media (ca. buffer capacity = 30 mM/ΔpH). In addition, it is valid provided no precipitation of its free form for salts (vice versa for free forms) in both the slurry pH measurement and at the dissolving drug surface. The formalized calculation scheme is simple and applicable to free and salt form drugs in unbuffered and buffered media including bicarbonate buffer. The computational expense is very small so that it is applicable to various computer simulations such as biopharmaceutics modeling and simulation.
Topics: Biopharmaceutics; Drug Liberation; Hydrogen-Ion Concentration; Pharmaceutical Preparations; Solubility
PubMed: 34637897
DOI: 10.1016/j.ejps.2021.106037 -
European Journal of Pharmaceutical... Jul 2021The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced... (Review)
Review
The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
Topics: Administration, Oral; Aged; Child; Female; Food-Drug Interactions; Gastrointestinal Tract; Humans; Intestinal Absorption; Male; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 33753215
DOI: 10.1016/j.ejps.2021.105812 -
Planta Medica Oct 2013Dioscorea villosa (wild yam) is native to North America and has been widely used as a natural alternative for estrogen replacement therapy to improve women's health as...
Dioscorea villosa (wild yam) is native to North America and has been widely used as a natural alternative for estrogen replacement therapy to improve women's health as well as to treat inflammation, muscle spasm, and asthma. Diosgenin and dioscin (glycoside form of diosgenin) are reported to be the pharmacologically active compounds. Despite the reports of significant pharmacological properties of dioscin and diosgenin in conditions related to inflammation, cancer, diabetes, and gastrointestinal ailments, no reports are available on ADME properties of these compounds. This study was carried out to determine ADME properties of diosgenin and dioscin and their effects on major drug metabolizing enzymes (CYP 3A4, 2D6, 2C9, and 1A2). The stability was determined in simulated gastric and intestinal fluids (SGF, pH 1.2 and SIF, pH 6.8), and intestinal transport was evaluated in Caco-2 model. Phase I and phase II metabolic stability was determined in human liver microsomes and S9 fractions, respectively. Quantitative analysis of dioscin and diosgenin was performed by UPLC-MS system. Dioscin degraded up to 28.3 % in SGF and 12.4 % in SIF, which could be accounted for by its conversion to diosgenin (24.2 %. in SGF and 2.4 % in SIF). The depletion of diosgenin in SGF and SIF was < 10 %. Diosgenin was stable in HLM but disappeared in S9 fraction with a half-life of 11.3 min. In contrast, dioscin was stable in both HLM and S9 fractions. Dioscin showed higher permeability across Caco-2 monolayer with no significant efflux, while diosgenin was subjected to efflux mediated by P-glycoprotein. Diosgenin and dioscin inhibited CYP3A4 with IC50 values of 17 and 33 µM, respectively, while other CYP enzymes were not affected. In conclusion, dioscin showed better intestinal permeability. Conversion of dioscin to diosgenin was observed in both gastric and intestinal fluids. No phase I metabolism was detected for both compounds. The disappearance of diosgenin in S9 fraction indicated phase II metabolism.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Anti-Inflammatory Agents; Caco-2 Cells; Cytochrome P-450 CYP3A; Dioscorea; Diosgenin; Half-Life; Humans; Inhibitory Concentration 50; Intestinal Absorption; Metabolic Detoxication, Phase II; Parasympatholytics; Permeability; Plant Extracts
PubMed: 23970424
DOI: 10.1055/s-0033-1350699 -
Journal of Clinical Pharmacology Jun 2023
Topics: Female; Humans; Pregnancy; Pharmacokinetics
PubMed: 37317493
DOI: 10.1002/jcph.2228 -
The Journal of Veterinary Medical... Oct 2023The aim of this study was to measure the concentrations of enrofloxacin (ERFX) and other fluoroquinolones; orbifloxacin (OBFX), marbofloxacin (MBFX), and ofloxacin...
The aim of this study was to measure the concentrations of enrofloxacin (ERFX) and other fluoroquinolones; orbifloxacin (OBFX), marbofloxacin (MBFX), and ofloxacin (OFLX) in the plasma and bile of rabbits after a single intravenous (IV) injection. Twenty male rabbits were divided into four groups and given each drug by IV injection into the ear vein at a dose of 5.0 mg/kg BW. The concentration of ERFX, ciprofloxacin (CPFX), OBFX, MBFX and OFLX in plasma and bile were determined by HPLC. CPFX, metabolite of ERFX, was also measured by HPLC in plasma and bile of rabbits receiving ERFX. Several pharmacokinetic parameters in plasma were calculated and biliary clearance (CL) was calculated from extent of biliary excretion and accumulation of AUC of each drug. After IV injection, elimination half-life (t) was 4.13, 3.68, 6.60, 5.14 hr; volume of distribution at a steady state (V) was 1.24, 0.503, 0.771, 1.02 L/kg; and total body clearance (CL) was 1.05, 0.418, 0.271, 0.453 L/kg/hr, respectively. The values for CL for ERFX, OBFX, MBFX, and OFLX were 0.0048, 0.0050, 0.0057, and 0.0094 L/kg/hr, respectively. These values represent 0.48%, 1.2%, 2.1%, and 2.3% of the total body clearance (CL) of each drug, respectively. The biliary clearance of CPFX was also measured and found to be 0.0199 L/kg/hr with ERFX administration. The results showed that ERFX, OBFX, MBFX, and OFLX were not excreted into the bile to a significant extent, making them safe drugs to use in rabbits.
Topics: Rabbits; Male; Animals; Injections, Intravenous; Hepatobiliary Elimination; Fluoroquinolones; Enrofloxacin; Area Under Curve; Half-Life
PubMed: 37635088
DOI: 10.1292/jvms.23-0246 -
Innovative approaches and recent advances in the study of ontogeny of drug metabolism and transport.British Journal of Clinical Pharmacology Oct 2022The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are... (Review)
Review
The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are subject to developmental changes reflecting growth and maturation along the paediatric continuum. However, knowledge gaps exist on these changes and their clinical impact. Filling these gaps may aid better prediction of drug disposition and creation of age-appropriate dosing guidelines. We present innovative approaches to study these developmental changes in relation to drug metabolism and transport. First, analytical methods such as including liquid chromatography-mass spectrometry for proteomic analyses allow quantitation of the expressions of a wide variety of proteins, e.g. membrane transporters, in a small piece of organ tissue. The latter is specifically important for paediatric research, where tissues are scarcely available. Second, innovative study designs using radioactive labelled microtracers allowed study-without risk for the child-of the oral bioavailability of compounds used as markers for certain drug metabolism pathways. Third, the use of modelling and simulation to support dosing recommendations for children is supported by both the European Medicines Agency and the US Food and Drug Administration. This may even do away with the need for a paediatric trial. Physiologically based pharmacokinetics models, which include age-specific physiological information are, therefore, increasingly being used, not only to aid paediatric drug development but also to improve existing drug therapies.
Topics: Biological Availability; Child; Computer Simulation; Humans; Metabolic Clearance Rate; Pharmaceutical Preparations; Proteomics
PubMed: 32851677
DOI: 10.1111/bcp.14534