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PloS One 2014Polyoxometalates are non-nucleoside analogs that have been proven to exhibit broad-spectrum antiviral activity. In particular, Cs2K4Na[SiW9Nb3O40].H2O 1 shows low...
Polyoxometalates are non-nucleoside analogs that have been proven to exhibit broad-spectrum antiviral activity. In particular, Cs2K4Na[SiW9Nb3O40].H2O 1 shows low toxicity and high activity against HBV. The preclinical pharmacokinetics of Compound 1 in rats were characterized by establishing and applying inductively coupled plasma-mass spectrometry method to determine the concentration of W in plasma, urine, feces, bile and organ samples. The quantitative ICP-MS method demonstrated good sensitivity and application in the pharmacokinetics study of polyoxometalates. The pharmacokinetic behavior of Compound 1 after intravenous or oral administration fit a two-compartment model. Tmax ranges from 0.1 h to 3 h and the T1/2 of Compound 1 is between 20 h and 30 h. The absolute bioavailability of Compound 1 at 45, 180 and 720 mg/kg groups were 23.68%, 14.67% and 11.93%, respectively. The rates of plasma protein binding of Compound 1 at 9, 18 and 36 mg/ml of Compound 1 are 62.13±9.41%, 71.20±24.98% and 49.00±25.59%, respectively. Compound 1 was widely distributed throughout the body, and high levels of compound 1 were found in the kidney and liver. The level of Compound 1 in excretion was lower: 30% for urine, 0.28% for feces and 0.42% for bile, respectively. For elaborate pharmacokinetic characteristics to be fully understood, the metabolism of Compound 1 needs to be studied further.
Topics: Animals; Antiviral Agents; Male; Metabolic Clearance Rate; Rats; Rats, Wistar; Tissue Distribution; Tungsten Compounds
PubMed: 24921932
DOI: 10.1371/journal.pone.0098292 -
Yao Xue Xue Bao = Acta Pharmaceutica... Apr 2014Pharmacokinetic analysis has attracted more and more attentions in the research field of bioactive natural product. However, there is limited study on the... (Review)
Review
Pharmacokinetic analysis has attracted more and more attentions in the research field of bioactive natural product. However, there is limited study on the pharmacokinetics of polysaccharides. This paper focused on the research progresses of pharmacokinetics of polysaccharide, summarized the applications of chromatography, isotope labeling method, spectrophotometry, fluorospectrophotometry and biological assay in the analysis of polysaccharide pharmacokinetics, elucidated the behaviors of absorption, distribution, degradation and excretion of polysaccharide in experimental animals, and revealed the effects of physicochemical characteristic, administration dose and route on the pharmacokinetic properties of polysaccharide, which could be served as a reference for the related works.
Topics: Administration, Oral; Animals; Injections; Intestinal Absorption; Metabolic Clearance Rate; Molecular Weight; Polysaccharides; Tissue Distribution
PubMed: 24974459
DOI: No ID Found -
Clinics in Laboratory Medicine Jun 1990Drugs ingested in overdose can have altered pharmacokinetics of absorption, distribution, and elimination. The pathophysiologic consequences of overdose can also change... (Review)
Review
Drugs ingested in overdose can have altered pharmacokinetics of absorption, distribution, and elimination. The pathophysiologic consequences of overdose can also change a drug's pharmacokinetic properties. Many toxicologic interventions are based on modifying the drug's pharmacokinetics (e.g., impairing absorption or enhancing elimination). Serum drug monitoring, even with its limitations, does have a role in managing the patient who has taken an overdose.
Topics: Absorption; Drug Overdose; Humans; Pharmacokinetics; Tissue Distribution
PubMed: 2197050
DOI: No ID Found -
Clinical Pharmacology in Drug... Jun 2023This was an open-label, randomized study in healthy Chinese participants to assess the bioequivalence of 2 fluconazole 150-mg capsules under fasted and fed conditions.... (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetics and Bioequivalence of Fluconazole Capsules Manufactured in France and China in Healthy Chinese Participants: Open-Label, Randomized, Single-Dose, 2-Way, Crossover Bioequivalence Study Under Fasted and Fed Conditions.
This was an open-label, randomized study in healthy Chinese participants to assess the bioequivalence of 2 fluconazole 150-mg capsules under fasted and fed conditions. The study consisted of 2 treatment periods, separated by a 14-day washout period. Thirty-six participants were enrolled, with 18 participants each in the fasted and fed groups. In each treatment period, participants received a single oral dose of the test or reference fluconazole 150-mg capsule. After washout, participants received the alternate treatment. Blood samples for pharmacokinetic analysis were collected from 1 hour before dosing to 72 hours after dosing. The median plasma concentration-time profiles were similar for both treatments under fasted and fed conditions. Bioequivalence of fluconazole between the 2 capsules was demonstrated as 90% confidence intervals of the geometric mean ratios for the maximum plasma concentration and area under the plasma concentration-time curve from time 0 to 72 hours after dosing under fasted and fed conditions were within the acceptable range of 80%-125%. Overall, 7 participants reported at least 1 treatment-emergent adverse event; all were mild in severity. No serious adverse events or deaths were reported. The test fluconazole capsule was bioequivalent to the reference capsule, and a single dose was well tolerated. Clinicaltrials.gov ID: NCT03621072.
Topics: Humans; Area Under Curve; Biological Availability; Cross-Over Studies; East Asian People; Fluconazole; Therapeutic Equivalency
PubMed: 37036155
DOI: 10.1002/cpdd.1248 -
Clinical Pharmacokinetics Dec 2000Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique... (Review)
Review
Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique pharmacokinetic characteristics among the members of this class. Many in vivo and in vitro human and animal studies suggest that active transport mechanisms are involved in the pharmacokinetics of pravastatin. The oral bioavailability of pravastatin is low because of incomplete absorption and a first-pass effect. The drug is rapidly absorbed from the upper part of the small intestine, probably via proton-coupled carrier-mediated transport, and then taken up by the liver by a sodium-independent bile acid transporter. About half of the pravastatin that reaches the liver via the portal vein is extracted by the liver, and this hepatic extraction is mainly attributed to biliary excretion which is performed by a primary active transport mechanism. The major metabolites are produced by chemical degradation in the stomach rather than by cytochrome P450-dependent metabolism in the liver. The intact drug and its metabolites are cleared through both hepatic and renal routes, and tubular secretion is a predominant mechanism in renal excretion. The dual routes of pravastatin elimination reduce the need for dosage adjustment if the function of either the liver or kidney is impaired, and also reduce the possibility of drug interactions compared with other statins. which are largely eliminated by metabolism. The lower protein binding than other statins weakens the tendency for displacement of highly protein-bound drugs. Although all statins show a hepatoselective disposition, the mechanism for pravastatin is different from that of the others. There is high uptake of pravastatin by the liver via an active transport mechanism, but not by other tissues because of its hydrophilicity, whereas the disposition characteristics of other statins result from high hepatic extraction because of high lipophilicity. These pharmacokinetic properties of pravastatin may be the result of the drug being given in the pharmacologically active open hydroxy acid form and the fact that its hydrophilicity is markedly higher than that of other statins. The nature of the pravastatin transporters, particularly in humans, remains unknown at present. Further mechanistic studies are required to establish the pharmacokinetic-pharmacodynamic relationships of pravastatin and to provide the optimal therapeutic efficacy for various types of patients with hypercholesterolaemia.
Topics: Adult; Aged; Aging; Area Under Curve; Biotransformation; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intestinal Absorption; Male; Pravastatin; Sex Characteristics; Tissue Distribution
PubMed: 11192473
DOI: 10.2165/00003088-200039060-00002 -
Clinical Pharmacokinetics 2008Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective... (Review)
Review
Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs. Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs whenever feasible. Variations in the extracellular fluid content as a response to the trauma of surgery and the fluid load or significant drug loss through thoracic drainages may significantly lower plasma concentrations of extracellularly distributed hydrophilic antimicrobials (beta-lactams, aminoglycosides and glycopeptides). Drug metabolism may be altered by the systemic inflammatory response and/or multiple organ failure and/or drug-drug pharmacokinetic interactions that can potentially occur during polytherapy, especially in immunosuppressed cardiac transplant patients. Instability of renal function may promote significant changes in body fluid concentrations of renally eliminated drugs, even in a brief period of hours. Finally, the application of extracorporeal circulation by means of cardiopulmonary bypass may significantly alter the disposition of several drugs during the operation because of acute haemodilution, hypoalbuminaemia, hypothermia and/or adsorption to the bypass equipment. Accordingly, to avoid either overexposure and the consequent increased risk of toxicity or underexposure and the consequent risk of therapeutic failure in critically ill cardiac patients, the dosing regimens of several drugs are expected to be significantly different from those suggested for clinically stable patients. Additionally, therapeutic drug monitoring may be helpful in the management of drug therapy and should be routinely used to guide individualized dose adjustments for (i) immunosuppressants whenever cytochrome P450 3A4 isoenzyme inhibitors (e.g. macrolide antibacterials, azole antifungals) or inducers (e.g. rifampicin [rifampin]) are added to or withdrawn from the regimen; and (ii) glycopeptide and aminoglycoside antibacterials whenever haemodynamically active agents (such as dopamine, dobutamine and furosemide [frusemide]) are added to or withdrawn from the regimen, and also whenever significant changes of haemodynamics and/or of renal function occur.
Topics: Cardiac Surgical Procedures; Cardiopulmonary Bypass; Critical Care; Humans; Intestinal Absorption; Intraoperative Period; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 18563954
DOI: 10.2165/00003088-200847070-00002 -
Current Drug Metabolism Nov 2008Strategies for optimising in vivo predictions from in vitro data on metabolic stability and CYP inhibition are discussed. Potential pitfalls and areas of inaccuracy are... (Review)
Review
Strategies for optimising in vivo predictions from in vitro data on metabolic stability and CYP inhibition are discussed. Potential pitfalls and areas of inaccuracy are highlighted together with recommendations for best practice. The use of both hepatic microsomes and isolated hepatocytes for the assessment of metabolic stability is discussed in terms of scaling from the in vitro system up to whole liver. The importance of integrating metabolic stability data together with other drug pharmacokinetic characteristics (e.g., protein binding and red blood cell uptake) as well as blood flow are presented within the context of different liver models. The assessment of CYP inhibition potential requires in vitro data on the inhibitor potency either in the form of Ki (for reversible inhibition) or KI and kinact (for time-dependent inhibition). The integration of these in vitro parameters together with other pharmacokinetic information is essential for the in vivo prediction. While a qualitative assessment may be made from the I/Ki ratio, a number of additional victim drug and enzyme-related parameters are required for quantitative prediction. Of particular importance is the parameter fmCYP (the fraction of the metabolic clearance of the victim drug that is catalyzed by the enzyme subject to the inhibition). Impact of other victim drug properties (e.g., fractional importance of the intestine) and enzyme properties (e.g., kdeg for time-dependent inhibition) on the drug-drug interaction prediction is discussed. In addition, mechanisms by which false negatives and false positives may result from in vitro strategies are summarized. Finally perspectives for future application and improvements in these predictions strategies are outlined.
Topics: Animals; Biotransformation; Drug Interactions; Forecasting; Humans; Metabolic Clearance Rate; Models, Statistical; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 18991591
DOI: 10.2174/138920008786485164 -
Clinical Cardiology Aug 1991Benazepril is a prodrug that, following rapid conversion to benazeprilat, is a potent nonsulfhydryl inhibitor of angiotensin-converting enzyme. The absorption,... (Review)
Review
Benazepril is a prodrug that, following rapid conversion to benazeprilat, is a potent nonsulfhydryl inhibitor of angiotensin-converting enzyme. The absorption, bioactivation, distribution, and elimination of benazepril and benazeprilat have been evaluated in healthy subjects, hypertensive patients, and patients with characteristics known to alter the pharmacokinetic disposition of ACE inhibitors, such as renal impairment, hepatic impairment, and advanced age. Following oral administration, benazepril is absorbed and transformed into benazeprilat in the liver. Coadministration of benazepril with food delays absorption slightly but does not affect the ultimate bioavailability of benazeprilat. Severe hepatic impairment slows conversion of benazepril to benazeprilat but does not affect the overall bioavailability of benazeprilat; thus dosage adjustment is not necessary in the hepatically impaired population. Mild-to-moderate renal impairment (creatinine clearance greater than 30 ml/min) slightly increases benazeprilat concentrations; severe renal impairment (creatinine clearance less than 30 ml/min) reduces benazeprilat elimination and requires dosage reduction. In elderly patients, benazepril disposition is the same as in younger patients, although benazeprilat clearance is slightly reduced. No clinically significant drug-drug interactions occur with benazepril and many other medications commonly prescribed to elderly hypertensive patients. The pharmacokinetic characteristics of benazepril are stable over a wide range of conditions, and dosage adjustments for pharmacokinetic reasons are required infrequently.
Topics: Absorption; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Biological Availability; Humans
PubMed: 1893642
DOI: 10.1002/clc.4960141807 -
Clinical Pharmacokinetics 2003Variability in the rate and extent of absorption, distribution and elimination of ethanol has important ramifications in clinical and legal medicine. The speed of... (Review)
Review
Variability in the rate and extent of absorption, distribution and elimination of ethanol has important ramifications in clinical and legal medicine. The speed of absorption of ethanol from the gut depends on time of day, drinking pattern, dosage form, concentration of ethanol in the beverage, and particularly the fed or fasting state of the individual. During the absorption phase, a concentration gradient exists between the stomach, portal vein and the peripheral venous circulation. First-pass metabolism and bioavailability are difficult to assess because of dose-, time- and flow-dependent kinetics. Ethanol is transported by the bloodstream to all parts of the body. The rate of equilibration is governed by the ratio of blood flow to tissue mass. Arterial and venous concentrations differ as a function of time after drinking. Ethanol has low solubility in lipids and does not bind to plasma proteins, so volume of distribution is closely related to the amount of water in the body, contributing to sex- and age-related differences in disposition. The bulk of ethanol ingested (95-98%) is metabolised and the remainder is excreted in breath, urine and sweat. The rate-limiting step in oxidation is conversion of ethanol into acetaldehyde by cytosolic alcohol dehydrogenase (ADH), which has a low Michaelis-Menten constant (Km) of 0.05-0.1 g/L. Moreover, this enzyme displays polymorphism, which accounts for racial and ethnic variations in pharmacokinetics. When a moderate dose is ingested, zero-order elimination operates for a large part of the blood-concentration time course, since ADH quickly becomes saturated. Another ethanol-metabolising enzyme, cytochrome P450 2E1, has a higher Km (0.5-0.8 g/L) and is also inducible, so that the clearance of ethanol is increased in heavy drinkers. Study design influences variability in blood ethanol pharmacokinetics. Oral or intravenous administration, or fed or fasted state, might require different pharmacokinetic models. Recent work supports the need for multicompartment models to describe the disposition of ethanol instead of the traditional one-compartment model with zero-order elimination. Moreover, appropriate statistical analysis is needed to isolate between- and within-subject components of variation. Samples at low blood ethanol concentrations improve the estimation of parameters and reduce variability. Variability in ethanol pharmacokinetics stems from a combination of both genetic and environmental factors, and also from the nonlinear nature of ethanol disposition, experimental design, subject selection strategy and dose dependency. More work is needed to document variability in ethanol pharmacokinetics in real-world situations.
Topics: Algorithms; Animals; Biotransformation; Central Nervous System Depressants; Ethanol; Humans; Intestinal Absorption; Tissue Distribution
PubMed: 12489977
DOI: 10.2165/00003088-200342010-00001 -
International Journal of Clinical... Jan 2023The aims of this study were to evaluate and compare the pharmacokinetic profiles and bioequivalence of two tablet formulations of methylprednisolone (test formulation:... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
The aims of this study were to evaluate and compare the pharmacokinetic profiles and bioequivalence of two tablet formulations of methylprednisolone (test formulation: Zhejiang Xianju Pharmaceutical Co., Ltd., China; reference formulation: Medrol, Pfizer Italia SRL) in healthy Chinese subjects under fasting and fed conditions.
MATERIALS AND METHODS
Subjects were randomly allocated to either the fasting group or the fed group and also to one of two sequences (test-reference or reference-test), according to which they received a single 16-mg dose of the test or reference methylprednisolone tablet in the study periods. Blood samples were collected pre dose and at intervals up to 16 hours after administration. Plasma methylprednisolone concentrations were determined using a validated liquid chromatography tandem mass spectrometry method. The safety of the medications was monitored throughout the study. The primary pharmacokinetic parameters measured were C, AUC, and AUC.
RESULTS
A total of 56 subjects were enrolled, and all completed the study. The 90% confidence intervals for C, AUC, and AUC, measured under both fasting and fed conditions, fell within the acceptable range for bioequivalence of 80 - 125%. Analysis of variance showed that there were no significant differences in the primary pharmacokinetic parameters (C, AUC, and AUC) between the test and reference formulation measured under both fasted and fed conditions. No serious or unexpected adverse drug reactions occurred during the study period.
CONCLUSION
The test methylprednisolone 16 mg tablet produced in China is bioequivalent to the reference formulation (Medrol) in healthy Chinese subjects measured under both fasting and fed conditions. Both formulations were well tolerated by all study participants.
Topics: Humans; Area Under Curve; Cross-Over Studies; East Asian People; Fasting; Healthy Volunteers; Tablets; Therapeutic Equivalency; Methylprednisolone
PubMed: 36278293
DOI: 10.5414/CP204076