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Journal of Veterinary Pharmacology and... Apr 2012Drugs containing one or more chiral centres exist in stereoisomeric molecular forms. Most commonly, drugs containing a single asymmetric carbon atom exist in two... (Review)
Review
Drugs containing one or more chiral centres exist in stereoisomeric molecular forms. Most commonly, drugs containing a single asymmetric carbon atom exist in two enantiomeric forms, designated as eutomer (the more potent) and distomer (the less potent). As well as differences in potency and other pharmacodynamic properties, most members of enantiomeric pairs commonly differ also in their pharmacokinetic profiles. This article reviews factors underlying differences in pharmacological properties of enantiomers. The relevance of such differences for studies designed to evaluate the bioequivalence of products containing chiral drugs is also reviewed.
Topics: Animals; Molecular Structure; Stereoisomerism; Structure-Activity Relationship; Therapeutic Equivalency; Veterinary Drugs
PubMed: 22413788
DOI: 10.1111/j.1365-2885.2012.01367.x -
American Journal of Veterinary Research Jul 2022To determine the pharmacokinetics, bioavailability, and pharmacological effects of cannabidiol (CBD) in senior horses.
OBJECTIVE
To determine the pharmacokinetics, bioavailability, and pharmacological effects of cannabidiol (CBD) in senior horses.
ANIMALS
8 university-owned senior horses.
PROCEDURES
In this randomized, crossover study, horses were assigned to receive either a single oral dose of 2 mg/kg CBD in oil or a single IV dose of 0.1 mg/kg CBD in DMSO between August 10 and September 4, 2020. Blood samples were collected before and then 0.5, 1, 4, 8, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 264 hours after CBD administration. Serum biochemical analyses and CBCs were performed. Plasma concentrations of CBD and its metabolites were determined with the use of liquid chromatography-tandem mass spectrometry.
RESULTS
Concentrations of CBD and metabolites (7-COH CBD and 7-COOH CBD) were detected in all plasma samples up to 8 hours after dosing (oral and IV), with 7-COOH CBD being the most predominant metabolite. Pharmacokinetic results for CBD oral dosing at 2 mg/kg were mean ± SD half-life of 7.22 ± 2.86 hours, maximum concentration of 18.54 ± 9.80 ng/mL, and time to maximum concentration of 2.46 ± 1.62 hours. For both oral and IV administrations, 7-COOH CBD did not fall below the limit of quantification for the times reported. Oral bioavailability for CBD was 7.92%. There was no meaningful effect of CBD on results for CBC, serum biochemical analyses, or vital signs for any horse.
CLINICAL RELEVANCE
Pharmacokinetics and bioavailability of CBD in senior horses were determined, and there were no adverse effects of administering either the oral or IV dose of CBD evaluated.
Topics: Animals; Administration, Oral; Area Under Curve; Biological Availability; Cannabidiol; Cross-Over Studies; Horses
PubMed: 35895770
DOI: 10.2460/ajvr.22.02.0028 -
Journal of Pharmacokinetics and... Dec 2010A number of experimental observations in the late 1960s, early 1970s could not be explained by the pharmacokinetic theory available at that time. For example rats... (Review)
Review
A number of experimental observations in the late 1960s, early 1970s could not be explained by the pharmacokinetic theory available at that time. For example rats receiving phenobarbital as an enzyme inducing agent exhibited increased elimination of phenylbutazone in vitro in liver microsomes and in vivo in whole animals compared to that observed in non-induced animals. However, for desipramine, although phenobarbital increased elimination in microsomes, no change in plasma disappearance was noted in vivo for this drug between rats induced with phenobarbital and control rats. Similar in vitro-in vivo discordancies were seen with changes in protein binding. The introduction of clearance concepts in the early 1970s by Professor Rowland and others provided the scientific rationale for these apparently contradictory findings and the recognition that clearance, not half-life, was the measure of the body's ability to eliminate drugs and most importantly that changes in pathology and physiology could be correlated with measures of clearance. Up to that time half-life was well recognized in terms of basic chemical principles as an appropriate measure of the rate of elimination and reflective of changes in the rate of elimination. The difference between chemistry and pharmacokinetics, however, is that in chemistry the volume in which the reaction occurs does not change. In contrast, in pharmacokinetics, disease states and differences in physiology can change the space available in which the drug may distribute in the body. Thus, it was necessary to develop a pharmacokinetic measure of volume that was independent of elimination, i.e., V(ss). Now, the relationship between V(ss) and clearance led to a unique measure of time of drug in the body, the mean residence time. Although this parameter is calculated in all PK programs, very few pharmaceutical scientists know how it can be useful. Very recently, we have shown that the concepts of accumulation, prediction of which is the clinically relevant use for half-life and mean residence time, are flawed and that the appropriate time dependent parameter to predict accumulation has not been previously correctly identified. Finally, when clearance concepts were developed our understanding of the importance of drug transporters was nonexistent. A critical, and generally unrecognized assumption (which is only explicitly stated in Professor Rowland's seminal 1973 paper), in the development of the theory of clearance is that the unbound drug concentration in the organ of elimination is in a constant equilibrium with the unbound drug concentration in the systemic circulation, where drug concentration measurements are made. Transporter drug-drug and disease interactions may, in fact, change this equilibrium and potentially what we consider as intrinsic clearance, may not be independent of an eliminating organ volume parameter, contrary to what we have been teaching for the past 37 years.
Topics: Animals; Drug Evaluation; Half-Life; Humans; Metabolic Clearance Rate; Models, Biological; Pharmacokinetics; Pharmacology, Clinical; Tissue Distribution
PubMed: 21113650
DOI: 10.1007/s10928-010-9187-8 -
The AAPS Journal Oct 2013A number of classical pharmacokinetic studies have been conducted in transplant patients. However, they suffer from some limitations, for example, (1) the study design... (Review)
Review
A number of classical pharmacokinetic studies have been conducted in transplant patients. However, they suffer from some limitations, for example, (1) the study design was limited to intense blood sampling in small groups of patients during a certain posttransplant period, (2) patient factors were evaluated one at a time to identify their association with the pharmacokinetic parameters, and (3) mean pharmacokinetic parameters often cannot be precisely estimated due to large intraindividual variability. Population pharmacokinetics provides a potential means of addressing these limitations and is a powerful tool to evaluate the magnitude and consistency of drug exposure. Population pharmacokinetic studies of cyclosporine focused solely on developing limited sampling strategies and Bayesian estimators to estimate drug exposure, have been summarized before, and are, therefore, not a subject of this review. The major focus of this review is to describe factors (demographic factors, hepatic and gastrointestinal functions, drug-drug interactions, genetic polymorphisms of drug metabolizing enzymes and transporters) that have been identified to contribute to the large portion of observed variability in the pharmacokinetics of cyclosporine in transplant patients. This review summarizes and interprets the conclusions as well as the nonlinear mixed-effects modeling methodologies used in such studies. A highly diversified collection of structural models, variability models, and covariate submodels have been evaluated and validated using internal or external validation methods. This review also highlights areas where additional research is warranted to improve the models since a portion of model variability still remains unexplained.
Topics: Animals; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Metabolic Clearance Rate; Organ Transplantation; Transplantation Immunology
PubMed: 23775356
DOI: 10.1208/s12248-013-9500-8 -
The AAPS Journal Apr 2013Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily... (Review)
Review
Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.
Topics: Animals; Biotransformation; Drug Administration Routes; Drug Discovery; Drug Dosage Calculations; Humans; Intestinal Absorption; Metabolic Clearance Rate; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics; Reproducibility of Results; Species Specificity; Tissue Distribution
PubMed: 23269526
DOI: 10.1208/s12248-012-9446-2 -
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 -
Drug Metabolism and Pharmacokinetics Dec 2004An attempt has been made to review the nonlinearities in the disposition in vitro, in situ, in loci and in vivo mainly from a theoretical point of view. Parallel... (Review)
Review
An attempt has been made to review the nonlinearities in the disposition in vitro, in situ, in loci and in vivo mainly from a theoretical point of view. Parallel Michaelis-Menten and linear (first-order) eliminations are often observed in the cellular uptake, metabolism and efflux of drugs. The well-stirred and parallel-tube models are mainly adopted under steady-state conditions in perfusion experiments, whereas distribution, tank-in-series and dispersion models are often used under nonsteady-state conditions with a pulse input. The analysis of the nonlinear local disposition in loci is reviewed from two points of view, namely an indirect method involving physiologically based pharmacokinetics (PBPK) and a direct (two or three samplings) method using live animals. The nonlinear global pharmacokinetics in vivo is reviewed with regard to absorption, elimination (metabolism and excretion) and distribution.
Topics: Algorithms; Area Under Curve; Cells, Cultured; Intestinal Absorption; Nonlinear Dynamics; Pharmacokinetics; Tissue Distribution
PubMed: 15681893
DOI: 10.2133/dmpk.19.397 -
Tidsskrift For Den Norske Laegeforening... Apr 2005
Topics: Absorption; Biological Availability; Gastrointestinal Motility; Humans; Intestinal Absorption; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 15815736
DOI: No ID Found -
Critical Reviews in Oncology/hematology Sep 2019Failure of systemic cancer treatment can be, at least in part, due to the drug not being delivered to the tumour at sufficiently high concentration and/or sufficiently... (Review)
Review
Failure of systemic cancer treatment can be, at least in part, due to the drug not being delivered to the tumour at sufficiently high concentration and/or sufficiently homogeneous distribution; this is termed as "pharmacokinetic drug resistance". To understand whether a drug is being adequately delivered to the tumour, "precision pharmacology" techniques are needed. Mass spectrometry imaging (MSI) is a relatively new and complex technique that allows imaging of drug distribution within tissues. In this review we address the applicability of MSI to the study of cancer drug distribution from the bench to the bedside. We address: (i) the role of MSI in pre-clinical studies to characterize anti-cancer drug distribution within the body and the tumour, (ii) the application of MSI in pre-clinical studies to define optimal drug dose or schedule, combinations or new drug delivery systems, and finally (iii) the emerging role of MSI in clinical research.
Topics: Antineoplastic Agents; Biological Availability; Diagnostic Imaging; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Delivery Systems; Drug Monitoring; Drug Resistance, Neoplasm; Humans; Mass Spectrometry; Neoplasms; Precision Medicine; Tissue Distribution
PubMed: 31302407
DOI: 10.1016/j.critrevonc.2019.06.008 -
BMC Pharmacology & Toxicology Feb 2023Ezetimibe is a new class of antihyperlipidemic agent indicated for the prevention of atherosclerosis disease and for the treatment of hypercholesterolemia. Information... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ezetimibe is a new class of antihyperlipidemic agent indicated for the prevention of atherosclerosis disease and for the treatment of hypercholesterolemia. Information on the pharmacokinetic profiles of ezetimibe tablet in healthy Chinese volunteers are lacking, and regulatory requirements necessitate a bioequivalence study of ezetimibe tablet versus Ezetrol® in China.
METHODS
A single-dose randomized, open-label, two-group, two-period crossover study was conducted in 59 healthy Chinese volunteers under fasting or fed conditions to assess the bioequivalence between two preparations. Eligible participants were randomly divided into fasted and fed groups. Blood samples were collected at specified time intervals, and the plasma concentrations of ezetimibe and ezetimibe glucuronide were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. PK and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded.
RESULTS
Fifty-nine healthy volunteers were enrolled in the study. The main pharmacokinetic parameters of total ezetimibe in the plasma of the ezetimibe tablet (10 mg) and the Ezetrol® (10 mg) after a single fasting administration: C were (65.73 ± 47.14), (71.32 ± 51.98) ng·mL; T were 1.75, 1.25 h; T½ were (17.09 ± 13.22), (17.35 ± 12.14) h; AUC were (643.34 ± 400.77), (668.49 ± 439.57) h·ng·mL; AUC were (706.36 ± 410.92), (734.23 ± 468.26) h·ng·mL. The main pharmacokinetic parameters of total ezetimibe in plasma of ezetimibe tablet (10 mg) and Ezetrol® (10 mg) after a fed administration: C were (83.38 ± 38.95), (84.74 ± 34.62) ng·mL; T were 2.50, 2.50 h; T½ were (22.56 ± 12.68), (19.80 ± 15.59) h; AUC were (494.21 ± 208.65), (536.69 ± 209.11) h·ng·mL; AUC were (573.74 ± 252.74), (604.75 ± 247.13) h·ng·mL. The main pharmacokinetic parameters C, AUC, and AUC of the two drugs were analyzed by variance analysis after logarithmic transformation. The total ezetimibe under fasting state with 90% confidence intervals (CIs) were 85.29 ~ 97.19, 90.41% ~ 104.38%, and 90.81 ~ 106.05%; total ezetimibe in fed state were 86.36% ~ 109.17, 84.96% ~ 96.40, and 85.32% ~ 101.0%. The 90% CIs of the ratio of geometric means (GMRs) of C, AUC, and AUC of Ezetrol® and ezetimibe tablet both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80-1.25. Both C and AUC met the predetermined criteria for assuming bioequivalence. No severe adverse events were observed.
CONCLUSIONS
The test ezetimibe tablet and Ezetrol® were determined to be bioequivalent under both fasting and fed conditions in Chinese people.
TRIAL REGISTRATION
Clinicaltrials, NCT05681247 (retrospectively registered in 11/01/ 2023).
Topics: Humans; Therapeutic Equivalency; Cross-Over Studies; Chromatography, Liquid; Ezetimibe; Healthy Volunteers; East Asian People; Tandem Mass Spectrometry; Area Under Curve; Fasting; Tablets
PubMed: 36737825
DOI: 10.1186/s40360-023-00649-y