Pharmacokinetics

摘要： With the interdisciplinary development of multiple disciplines,mathematical models play a role as a bridge in the research process of Chinese herbal compounds,which can make full use of the interrelationships of knowledge,making the research and use of Chinese herbal compounds from complex and cumbersome to simple.This paper reviewed the research and application of mathematical models in the production and preparation,pharmacodynamics,pharmacokinetics and other aspects of Chinese herbal compound prescriptions,providing a theoretical basis for the development of the modern Chinese medicine industry.

摘要： The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer’s disease.In this study,an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices.The plasma pharmacokinetics,tissue distribution,and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated.Despite its complicated structural composition,the absorption,distribution,metabolism,and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate.Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration,with very low oral bioavailability in rats(0.6%-1.6%)and dogs(4.5%-9.3%).Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues.Sodium oligomannate could penetrate the blood-cerebrospinal fluid(CSF)barrier of rats,showing a constant area under the concentration-time curve ratio(CSF/plasma)of approximately 5%.The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability,supporting that excretion was predominantly renal,whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats.Moreover,only 33.7%(male)and 26.3%(female)of the oral dose were recovered in the rat excreta within 96 h following a single oral administration,suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.

摘要： Leukovir, an enteric-coated tablet, is the original drug product for internal use. The well-known nucleosides cladribine and ribavirin are the active ingredients of the drug product leukovir. Pharmacokinetic parameters of the drug product for the internal use of leukovir active ingredients have been established. The cladribine half-absorption period was t1/2a = 49.5 h, C0 = 276.4 μg/ml, Cmax = 6.0 μg/ml. Distribution and accumulation parameters (Vd, Vss and AUC) have indicated that the drug distribution between the blood cells and blood plasma takes place in the same way, irrespective of the dosage form. Cladribine half-life period is t1/2e = 0.62 hours. The molecule total clearance and average lifetime in the body in the case of subcutaneous drug administration are approximately the same. Ribavirin is characterized by a half-absorption period of t1/2a = 0.71 h, C0 = 115.6 μg/ml and Cmax = 75.5 μg/ml. Ribavirin total volume of distribution (Vd = 1.3 l/kg) and stationary volume of distribution (Vss = 1.64 l/kg) were practically similar to leukovir when administered subcutaneously. The AUC value = 504.2 μg h/ml, which is 2.5 times less than that in the case of drug form administration. Leukovir was regarded as slightly toxic in an acute toxicity study. The risk of cumulation for this drug product is low.

摘要： Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.

摘要： Pharmacokinetic compartment models are the only models that can extract pharmacokinetic parameters from data collected in clinical studies but their estimates lack accuracy, explanations and physiological significance. The objective of this work was to develop particular solutions to drug concentration and AUC in the form of mathematical series and Heaviside functions for repetitive intermittent infusions in the one- and two-compartment models, as a function of dose number and total time using differential calculus. It was demonstrated that the central and peripheral compartment volumes determined from regression analysis of the aminoglycoside antibiotic Sisomicin concentration in plasma represent the actual physiological body fluid volumes accessible by the drug. The drug peak time and peak concentration in the peripheral compartment were also calculated as a function of dose number. It is also shown that the time of intercompartmental momentary distribution equilibrium can be used to determine the drug’s apparent volume of distribution within any dosing interval in multi-compartment models. These estimates were used to carry out simulations of plasma drug concentration with time in the one-compartment model. In conclusion, the two-compartment open mammillary pharmacokinetic model was fully explained for the aminoglycoside antibiotic sisomicin through the new concept of the apparent volume of distribution.

摘要： BACKGROUND Vancomycin is the most commonly used drug for methicillin-resistant Staphylococcus aureus.The empirical clinical doses of vancomycin based on non-obese patients may not be optimal for obese ones.CASE SUMMARY This study reports a case of vancomycin dosing adjustment in an obese patient(body mass index 78.4 kg/m2)with necrotizing fasciitis of the scrotum and left lower extremity accompanied with acute renal failure.Dosing adjustment was performed based on literature review and factors that influence pharmacokinetic parameters are analyzed.The results of the blood drug concentration monitoring confirmed the successful application of our dosing adjustment strategy in this obese patient.Total body weight is an important consideration for vancomycin administration in obese patients,which affects the volume of distribution and clearance of vancomycin.The alterations of pharmacokinetic parameters dictate that vancomycin should be dose-adjusted when applied to obese patients.At the same time,the pathophysiological status of patients,such as renal function,which also affects the dose adjustment of the patient,should be considered.CONCLUSION Monitoring vancomycin blood levels in obese patients is critical to help adjust the dosing regimen to ensure that vancomycin concentrations are within the effective therapeutic range and to reduce the incidence of renal injury.

摘要： Mesenchymal stem cells(MSCs)represent an important tool in veterinary regenerative medicine due to their ability to home to injury sites and secrete molecules that regulate niches into regenerative microenvironments.Successful cell therapy depends on many factors,including choice of administration route and application of understanding of cell potency and their therapeutic mechanisms.In this point of view,the authors leverage the tumultuous history of the field to demonstrate the need for clinicians to continually update themselves as new discoveries are made in order to avoid misalignments in the future,especially regarding administration routes and dose frequency,as well as to explore recent insights into MSC plasticity,therapeutic mechanisms,and cell delivery systems.

摘要： Background: Telmisartan is a highly variable drug which is used to treat hypertension. This study compared to compare the bioavailability of two 40 mg Telmisartan tablets in adult and healthy Bangladeshi subjects. Materials and Method: This study was open label, randomized, laboratory blind, single dose, three periods, two treatments, three-sequence, partial-replicate, crossover and comparative oral bioavailability study. In this study, 18 Bangladeshi subjects were enrolled and 17 subjects were completed. Serial blood samples were collected up to 96 hours following drug administration. By using Liquid Chromatography Mass Spectrometry (LC-MS/MS) method, plasma concentrations of Telmisartan were determined. Results: The two formulations of Telmisartan were considered bioequivalent if 90% Confidence Interval (CI) fall within the range of 80.00% - 125.00% for AUC parameters and reference-scaled-average bioequivalence of 69.84% - 143.19% for Cmax. The 90% Confidence Interval for Cmax, AUC0-t & AUC0-∞ was found 84.88% - 107.79%, 89.76% - 109.55%, and 91.20% - 114.52%, respectively. Conclusion: According to rate and extent of absorption with the single dose of Reference Product (R): Micardis? 40 mg Tablet, under fasting conditions, a single dose of Telmisartan 40 mg Tablet is bioequivalent.

摘要： A fast,reliable,and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019,namely,Lianhua Qingwen granules,Huoxiang Zhengqi capsules,Jinhua Qinggan granules,Shufeng Jiedu capsules,and Angong Niuhuang pills,on the pharmacokinetics of lopinavir/ritonavir in rats.Blood samples were prepared using the protein precipitation method and atazanavir was selected as the internal standard(IS).Separation was performed on an Agilent ZORBAX eclipse plus C18(2.1 mm×50 mm,1.8 μm)column using acetonitrile and water containing 0.1%formic acid as the mobile phase for gradient elution.The flow rate was 0.4 mL/min and the injection volume was 2 μL.Agilent Jet Stream electrospray ionization was used for mass spectrometry detection under positive ion multiple reaction monitoring mode at a transition of m/z 629.3→447.3 for lopinavir,m/z 721.3→296.1 for ritonavir,and m/z 705.4→168.1 for the IS.The method showed good linearity in the concentration range of 25→2500 ng/mL(r=0.9981)for lopinavir and 5e500 ng/mL(r=0.9984)for ritonavir.The intra-day and inter-day precision and accuracy were both within±15%.Items,such as dilution reliability and residual effect,were also within the acceptable limits.The method was used to determine the effects of five types of traditional Chinese medicines on the pharmacokinetics of lopinavir/ritonavir in rats.The pharmacokinetic results showed that the half-life of ritonavir in the groups administered Lianhua Qingwen granules and Huoxiang Zhengqi capsules combined with lopinavir/ritonavir was prolonged by approximately 1.5-to 2-fold relative to that in the control group.Similarly,the pharmacokinetic parameters of lopinavir were altered.Overall,the results of this study offer important theoretical parameters for the effective clinical use of five types of traditional Chinese medicines combined with lopinavir/ritonavir to reduce the occurrence of clinical adverse reactions.

摘要： Chito-oligosaccharide(COS)had shown a variety of biological activities and potential biomedical implications.The present study investigated the pharmacokinetics,bioavailability,and in vitro absorption of COS with degrees of polymerization(DPs)2-7 and explored the influence of DPs on them.From Caco-2 cell permeation studies,COS were low permeability compounds with no directional effects,suggesting a low in vivo absorption mediated by facilitation diffusion and paracellular absorption.After an intragastrical administration to rats,COS2 showed the highest systemic exposure in six oligosaccharides.The bioavailability of COS2-7 was 7.33%,6.11%,4.67%,4.13%,4.02%,0.99%,respectively.Differences in bioavailability for each COS correlated to structural variations,with high DPs contributing to a decrease in bioavailability.In conclusion,COS could be absorbed by the intestinal tract both in vitro and in vivo.The very low oral bioavailability of COS could be due to low permeability.DPs can affect absorption and bioavailability of COS2-7.This study provided evidence for the absorption characteristics of COS2-7 to help us better understanding the pharmacological actions.