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Basic & Clinical Pharmacology &... Aug 2013Early understanding of the pharmacokinetics and metabolic patterns of new drug candidates is essential for selection of optimal candidates to move further in to the drug... (Review)
Review
Early understanding of the pharmacokinetics and metabolic patterns of new drug candidates is essential for selection of optimal candidates to move further in to the drug development process. In vitro methodologies can be used to investigate metabolic patterns, but in general, they lack several aspects of the whole-body physiology. In contrast, the complexity of intact animals does not necessarily allow individual processes to be identified. Animal models lacking a major excretion organ can be used to investigate these individual metabolic processes. Animal models of nephrectomy and hepatectomy have considerable potential as tools in preclinical pharmacokinetics to assess organs of importance for drug clearance and thereby knowledge of potential metabolic processes to manipulate to improve pharmacokinetic properties of the molecules. Detailed knowledge of anatomy and surgical techniques is crucial to successfully establish the models, and a well-balanced anaesthesia and adequate monitoring of the animals are also of major importance. An obvious drawback of animal models lacking an organ is the disruption of normal homoeostasis and the induction of dramatic and ultimately mortal systemic changes in the animals. Refining of the surgical techniques and the post-operative supportive care of the animals can increase the value of these models by minimizing the systemic changes induced, and thorough validation of nephrectomy and hepatectomy models is needed before use of such models as a tool in preclinical pharmacokinetics. The present MiniReview discusses pros and cons of the available techniques associated with establishing nephrectomy and hepatectomy models.
Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Hepatectomy; Humans; Metabolic Clearance Rate; Nephrectomy; Pharmacokinetics; Tissue Distribution
PubMed: 23586405
DOI: 10.1111/bcpt.12077 -
The Journal of Pharmacology and... Sep 2019The use of drug delivery systems (DDS) is an attractive approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when free drug... (Review)
Review
The use of drug delivery systems (DDS) is an attractive approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when free drug has poor pharmacokinetics/biodistribution (PK/BD) or significant off-site toxicities. Successful translation of DDS into the clinic is dependent on a thorough understanding of the in vivo behavior of the carrier, which has, for the most part, been an elusive goal. This is, at least in part, due to significant differences in the mechanisms controlling pharmacokinetics for classic drugs and DDSs. In this review, we summarize the key physiologic mechanisms controlling the in vivo behavior of DDS, compare and contrast this with classic drugs, and describe engineering strategies designed to improve DDS PK/BD. In addition, we describe quantitative approaches that could be useful for describing PK/BD of DDS, as well as critical steps between tissue uptake and pharmacologic effect.
Topics: Animals; Drug Delivery Systems; Drug Therapy; Humans; Pharmacokinetics; Pharmacology; Tissue Distribution
PubMed: 30837281
DOI: 10.1124/jpet.119.257113 -
BMC Veterinary Research Apr 2022Buserelin is a luteinizing hormone releasing hormone (LHRH) agonist used for the treatment of hormone-dependent diseases in males and females. However, the...
BACKGROUND
Buserelin is a luteinizing hormone releasing hormone (LHRH) agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not fully understood. This study was designed to develop a sensitive method to determine the concentration of buserelin in blood plasma and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows.
RESULTS
A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studied in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC) was 25.02 ± 6.93 h × ng/mL for pigs and 5.63 ± 1.86 h × ng/mL for cows. The maximum plasma concentration (C) and time to reach the maximum concentration (t) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ± 0.27 h for cows, respectively. The apparent volume of distribution (V) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals.
CONCLUSION
This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.
Topics: Animals; Area Under Curve; Biological Availability; Buserelin; Cattle; Chromatography, Liquid; Female; Male; Swine; Tandem Mass Spectrometry
PubMed: 35410205
DOI: 10.1186/s12917-022-03237-0 -
The Journal of Pharmacology and... Feb 2021A semimechanistic physiologically based pharmacokinetic (PBPK) model for chloroquine (CQ), a highly lysosomotropic weak base, was applied to digitized rat and human...
A semimechanistic physiologically based pharmacokinetic (PBPK) model for chloroquine (CQ), a highly lysosomotropic weak base, was applied to digitized rat and human concentration versus time data. The PBPK model in rat featured plasma and red blood cell (RBC) concentrations, extensive and apparent nonlinear tissue distribution, fitted hepatic and renal intrinsic clearances, and a plasma half-life of about 1 day. Tissue-to-plasma CQ ratios at 50 hours after dosing were highest in lung, kidney, liver, and spleen (182-318) and lower in heart, muscle, brain, eye, and skin (11-66). The RBC-to-plasma ratio of 11.6 was assumed to reflect cell lipid partitioning. A lysosome-based extended model was used to calculate subcellular CQ concentrations based on tissue mass balances, fitted plasma, interstitial and free cytosol concentrations, and literature-based pH and pKa values. The CQ tissue component concentrations ranked as follows: lysosome > > acidic phospholipid > plasma = interstitial = cytosol ≥ neutral lipids. The extensive lysosome sequestration appeared to change over time and was attributed to lowering pH values caused by proton pump influx of hydrogen ions. The human-to-rat volume of distribution () ratio of 7 used to scale rat tissue partitioning to human along with estimation of hepatic clearance allowed excellent fitting of oral-dose PK (150-600 mg) of CQ with a 50-day half-life in humans. The prolonged PK of chloroquine was well characterized for rat and human with this PBPK model. The calculated intratissue concentrations and lysosomal effects have therapeutic relevance for CQ and other cationic drugs. SIGNIFICANCE STATEMENT: Sequestration in lysosomes is a major factor controlling the pharmacokinetics and pharmacology of chloroquine and other cationic drugs. This report provides comprehensive physiologic modeling of chloroquine distribution in tissues and overall disposition in rat and human that reveals expected complexities and inferences related to its subcellular association with various tissue components.
Topics: Animals; Antimalarials; Brain; Chloroquine; Erythrocytes; Hepatobiliary Elimination; Humans; Lysosomes; Models, Theoretical; Muscles; Myocardium; Rats; Renal Elimination; Species Specificity; Tissue Distribution
PubMed: 33277347
DOI: 10.1124/jpet.120.000385 -
European Review For Medical and... Dec 2023Amiodarone (AMD), a drug of choice to treat cardiac arrhythmias, has a narrow therapeutic index (NTI). It inhibits CYP3A4, CYP2C9, and CYP2D6 enzymes. Quercetin (QUE), a...
OBJECTIVE
Amiodarone (AMD), a drug of choice to treat cardiac arrhythmias, has a narrow therapeutic index (NTI). It inhibits CYP3A4, CYP2C9, and CYP2D6 enzymes. Quercetin (QUE), a pharmacologically important bioflavonoid in vegetables and fruits, is important in treating cardiovascular comorbidities. QUE alters the bioavailability of drugs used concurrently by dual inhibition of P-glycoproteins (P-gp) and cytochrome (CYP) enzyme systems. The current study aimed to investigate the pre-treatment and co-administration effect of QUE on AMD pharmacokinetics in rats.
MATERIALS AND METHODS
Two separate animal trials (I and II) were planned to probe the effect of QUE on AMD pharmacokinetics by following previously cited studies. The pre-treatment group received oral doses of QUE for 14 days, and a single dose of AMD on the 15th day. Rats were administered single doses of QUE (20 mg/kg) and AMD (50 mg/kg) concurrently in a carboxymethylcellulose (CMC) in the co-administration study. Blood was collected at pre-determined time points. AMD was quantified by HPLC, and data was analyzed by PK solver software.
RESULTS
In the pre-treated group, peak plasma concentration (Cmax) and area under the curve (AUC0-∞) of AMD were increased by 45.52% and 13.70%, respectively, while time to achieve maximum concentration (tmax), half-life (t1/2) and clearance (CL) were declined by 35.72%, 16.75%, and 11.0% respectively compared to the control. In the co-administered group, compared to controls, Cmax and AUC0-∞ were elevated to 12.90% and 7.80%, respectively, while tmax, t1/2, and CL declined by 16.70%, 2.35%, and 13.40%. Further, AMD was increased in lung tissue of both treated groups, relative to the respective controls.
CONCLUSIONS
A notable pharmacokinetic drug interaction between QUE and AMD was observed in rats and warrants possible drug interaction study in humans, suggesting AMD dose adjustment specifically in patients with arrhythmia having a pre-treatment history and simultaneous administration of QUE-containing products.
Topics: Humans; Rats; Animals; Quercetin; Amiodarone; Tissue Distribution; Drug Interactions; Biological Availability; Area Under Curve
PubMed: 38095371
DOI: 10.26355/eurrev_202312_34561 -
Drug Testing and Analysis Aug 2012This review provides a summary of those pharmacokinetic properties of veterinary drugs relevant to marker residues, marker tissues, and residue depletion rates. The... (Review)
Review
This review provides a summary of those pharmacokinetic properties of veterinary drugs relevant to marker residues, marker tissues, and residue depletion rates. The scientific literature in this field is very extensive and there is also a wealth of data available on the websites of various regulatory jurisdictions. Therefore, this review is limited to selected examples, cited to illustrate general principles. The areas considered are: (1) the relationship of dose to plasma concentration through the pharmacokinetic properties, area under plasma concentration-time curve, bioavailability, and clearance; (2) the critical dependence of drug pharmacokinetics and residue depletion on product formulation; (3) disease state and population pharmacokinetics; and (4) the requirement for residue depletion studies for generic products shown to be bioequivalent to pioneer products.
Topics: Animals; Biological Availability; Drug Residues; Therapeutic Equivalency; Veterinary Drugs
PubMed: 22851359
DOI: 10.1002/dta.1374 -
PloS One 2022Imidocarb (IMD) is commonly used for treatment of eperythrozoon, babesia, piroplasma and trypanosoma in animals, but there are few studies on its pharmacokinetics in...
Imidocarb (IMD) is commonly used for treatment of eperythrozoon, babesia, piroplasma and trypanosoma in animals, but there are few studies on its pharmacokinetics in cattle. The purpose of this study was to obtain pharmacokinetic parameters and assess the bioequivalence of subcutaneous injections of two IMD formulations in cattle. Forty-eight healthy cattle, 24 males and 24 females, were randomLy divided into two groups (test group and reference group) with 12 males and 12 females per group. The generic IMD was injected subcutaneously with a single dose of 3.0 mg/kg in the test group. Reference group animals were given one injection of the marketed IMD at the same dosage. The limit of detection (LOD) and limit of quantification (LOQ) for IMD in cattle plasma were 0.05 ng/mL and 0.1 ng/mL, respectively. The recoveries ranged from 88.50% to 92.42%, and the equation of this calibration curve was Y = 13672.1X+187.43. The pharmacokinetics parameters of the test group showed that the maximum concentration of 2257.5±273.62 ng/mL was obtained at 2.14±0.67 h, AUC0-t 14553.95±1946.85 ng·h/mL, AUC∞ 15077.88±1952.19 ng·h/mL, T1/2 31.77±25.75 h, CL/F 0.14±0.02 mL/h/g, and Vz/F 6.53±5.34 mL/g. There was no significant difference in AUC0-t, AUC∞ and Cmax between the test group and the reference group (P>0.05). The 90% confidence interval of AUC0-t, AUC0-∞ and Cmax in the test group was included in 80%-125% AUC0-t, AUC0-∞ and 70%-143% Cmax in the reference group, respectively. Based on these results, the two preparations were found to be bioequivalent.
Topics: Animals; Cattle; Female; Male; Area Under Curve; Cross-Over Studies; Imidocarb; Injections, Subcutaneous; Tablets; Therapeutic Equivalency
PubMed: 35749453
DOI: 10.1371/journal.pone.0270130 -
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 -
Pharmacological Reviews Apr 2020Technology in bioanalysis, , and computation have evolved over the past half century to allow for comprehensive assessments of the molecular to whole body pharmacology... (Review)
Review
Technology in bioanalysis, , and computation have evolved over the past half century to allow for comprehensive assessments of the molecular to whole body pharmacology of diverse corticosteroids. Such studies have advanced pharmacokinetic and pharmacodynamic (PK/PD) concepts and models that often generalize across various classes of drugs. These models encompass the "pillars" of pharmacology, namely PK and target drug exposure, the mass-law interactions of drugs with receptors/targets, and the consequent turnover and homeostatic control of genes, biomarkers, physiologic responses, and disease symptoms. Pharmacokinetic methodology utilizes noncompartmental, compartmental, reversible, physiologic [full physiologically based pharmacokinetic (PBPK) and minimal PBPK], and target-mediated drug disposition models using a growing array of pharmacometric considerations and software. Basic PK/PD models have emerged (simple direct, biophase, slow receptor binding, indirect response, irreversible, turnover with inactivation, and transduction models) that place emphasis on parsimony, are mechanistic in nature, and serve as highly useful "top-down" methods of quantitating the actions of diverse drugs. These are often components of more complex quantitative systems pharmacology (QSP) models that explain the array of responses to various drugs, including corticosteroids. Progressively deeper mechanistic appreciation of PBPK, drug-target interactions, and systems physiology from the molecular (genomic, proteomic, metabolomic) to cellular to whole body levels provides the foundation for enhanced PK/PD to comprehensive QSP models. Our research based on cell, animal, clinical, and theoretical studies with corticosteroids have provided ideas and quantitative methods that have broadly advanced the fields of PK/PD and QSP modeling and illustrates the transition toward a global, systems understanding of actions of diverse drugs. SIGNIFICANCE STATEMENT: Over the past half century, pharmacokinetics (PK) and pharmacokinetics/pharmacodynamics (PK/PD) have evolved to provide an array of mechanism-based models that help quantitate the disposition and actions of most drugs. We describe how many basic PK and PK/PD model components were identified and often applied to the diverse properties of corticosteroids (CS). The CS have complications in disposition and a wide array of simple receptor-to complex gene-mediated actions in multiple organs. Continued assessments of such complexities have offered opportunities to develop models ranging from simple PK to enhanced PK/PD to quantitative systems pharmacology (QSP) that help explain therapeutic and adverse CS effects. Concurrent development of state-of-the-art PK, PK/PD, and QSP models are described alongside experimental studies that revealed diverse CS actions.
Topics: Adrenal Cortex Hormones; Animals; Computational Biology; Humans; Models, Biological; Pharmacokinetics; Pharmacology
PubMed: 32123034
DOI: 10.1124/pr.119.018101 -
Nutrients Nov 2022Succinic acid is widely used as a food additive, and its effects on sepsis, cancer, ataxia, and obesity were recently reported. Dietary drug exposure studies have been...
Succinic acid is widely used as a food additive, and its effects on sepsis, cancer, ataxia, and obesity were recently reported. Dietary drug exposure studies have been conducted to evaluate the in vivo efficacy of succinic acid, but limited pharmacokinetic information is available. Therefore, this study evaluated the pharmacokinetic profiles and tissue distribution of succinic acid following a single intravenous or oral dose. A surrogate analyte, succinic acid-C (CSA), was administrated to distinguish endogenous and exogenous succinic acid. The concentration of CSA was determined by a validated analytical method using mass spectrometry. After a 10 mg/kg intravenous dose, non-compartmental pharmacokinetic analysis in plasma illustrated that the clearance, volume of distribution, and terminal half-life of CSA were 4574.5 mL/h/kg, 520.8 mL/kg, and 0.56 h, respectively. Oral CSA was absorbed and distributed quickly (bioavailability, 1.5%) at a dose of 100 mg/kg. In addition, CSA exposure was the highest in the liver, followed by brown adipose tissue, white adipose tissue, and the kidneys. This is the first report on the pharmacokinetics of succinic acid after a single dose in mice, and these results could provide a foundation for selecting dosing regimens for efficacy studies.
Topics: Mice; Animals; Tissue Distribution; Succinic Acid; Administration, Oral; Biological Availability; Administration, Intravenous
PubMed: 36432443
DOI: 10.3390/nu14224757