Comparison of toxicokinetic parameters of a drug and two metabolites following traditional and capillary microsampling in rat

Bioanalysis ◽  
2019 ◽  
Vol 11 (13) ◽  
pp. 1233-1242 ◽  
Author(s):  
Tom Verhaeghe ◽  
Lieve Dillen ◽  
Hans Stieltjes ◽  
Loeckie de Zwart ◽  
Bianca Feyen
Keyword(s):  
Large Volume ◽  
Regulatory Authority ◽  
Statistical Difference ◽  
Parent Drug ◽  
Pharmacokinetic Parameters ◽  
Sampling Techniques ◽  
Plasma Samples ◽  
Blood Samples ◽  
Rat Study ◽  
Different Doses

Aim: Following the request of a regulatory authority, a rat study was conducted to compare pharmacokinetic parameters from traditional large volume sampling and capillary microsampling. Materials & methods: Rats were dosed with a proprietary compound in three dose groups and blood samples were collected via capillary microsampling (32 μl), immediately followed by traditional large volume sampling (300 μl) up to 24 h postdose. Resulting plasma samples were analyzed for parent drug and two metabolites. AUCs were compared between sampling techniques. Results: There was no statistical difference between AUCs from traditional and microsampling across different doses and analytes. Conclusion: Toxicokinetic parameters generated from plasma collected as a capillary microsample or traditional large volume sample are highly comparable.

scholarly journals Effects of Plasma Albumin on the Pharmacokinetics of Esomeprazole in ICU Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-6
Author(s):  
Hsin Tian ◽  
Yanyan Xu ◽  
Jiayan Wang ◽  
Weiqiang Tian ◽  
Jian Sun ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Statistical Difference ◽  
High Plasma ◽  
Pharmacokinetic Parameters ◽  
Basilic Vein ◽  
Plasma Albumin ◽  
Icu Patients ◽  
Blood Samples ◽  
Time Points ◽  
Group B

Objectives. To evaluate the effects of plasma albumin on pharmacokinetics of esomeprazole in ICU patients. Methods. This study was performed in 32 consecutive intensive care unit (ICU) patients. They were divided into two groups according to the plasma albumin levels. Nineteen patients with low plasma albumin levels (<30 g/L; male/female, 12/7) were assigned to low plasma albumin group (LPAG). Thirteen patients with plasma albumin levels >30 g/L (male/female, 9/4) were assigned to high plasma albumin group (HPAG). All patients were received intravenous (IV) of 40 mg esomeprazole in 5 min. Blood samples were collected via basilic vein at different time points and concentrations of esomeprazole were determined by UPLC-MS/MS. Results. MRT(0-∞), t1/2, V, CL, and Cmax between two groups were significantly difference (P<0.05). Compared with HPAG, MRT(0-∞), t1/2, and V of esomeprazole in LPAG were increased by 1.42-fold, 1.49-fold, and 1.24-fold, respectively; the maximum drug concentration of esomeprazole in LPAG was decreased to 82.5%. AUC(0-∞) of LPAG was 1.23 times than that of group B. CL in LPAG was 80% of HPAG. There was no statistical difference between the two groups of AUC(0-∞) and CL. Conclusions. Some pharmacokinetic parameters of esomeprazole may be changed in ICU patients with low plasma albumin.

Stability of antioxidant vitamins in whole human blood during overnight storage at 4°C and frozen storage up to 6 months

2018 ◽  
Vol 88 (3-4) ◽  
pp. 151-157 ◽  
Author(s):  
Scott W. Leonard ◽  
Gerd Bobe ◽  
Maret G. Traber
Keyword(s):  
Ascorbic Acid ◽  
Whole Blood ◽  
Healthy Subjects ◽  
Frozen Storage ◽  
Blood Collection ◽  
Plasma Samples ◽  
Optimal Conditions ◽  
Plasma Ascorbic Acid ◽  
Blood Samples ◽  
Sample Handling

Abstract. To determine optimal conditions for blood collection during clinical trials, where sample handling logistics might preclude prompt separation of erythrocytes from plasma, healthy subjects (n=8, 6 M/2F) were recruited and non-fasting blood samples were collected into tubes containing different anticoagulants (ethylenediaminetetra-acetic acid (EDTA), Li-heparin or Na-heparin). We hypothesized that heparin, but not EDTA, would effectively protect plasma tocopherols, ascorbic acid, and vitamin E catabolites (α- and γ-CEHC) from oxidative damage. To test this hypothesis, one set of tubes was processed immediately and plasma samples were stored at −80°C, while the other set was stored at 4°C and processed the following morning (~30 hours) and analyzed, or the samples were analyzed after 6 months of storage. Plasma ascorbic acid, as measured using HPLC with electrochemical detection (LC-ECD) decreased by 75% with overnight storage using EDTA as an anticoagulant, but was unchanged when heparin was used. Neither time prior to processing, nor anticoagulant, had any significant effects upon plasma α- or γ-tocopherols or α- or γ-CEHC concentrations. α- and γ-tocopherol concentrations remained unchanged after 6 months of storage at −80°C, when measured using either LC-ECD or LC/mass spectrometry. Thus, refrigeration of whole blood at 4°C overnight does not change plasma α- or γ-tocopherol concentrations or their catabolites. Ascorbic acid is unstable in whole blood when EDTA is used as an anticoagulant, but when whole blood is collected with heparin, it can be stored overnight and subsequently processed.

scholarly journals Detection of Cyclospora cayetanensis in produce irrigation and wash water using large-volume sampling techniques

2021 ◽  
Vol 22 ◽  
pp. e00110
Author(s):  
Amy M. Kahler ◽  
Mia C. Mattioli ◽  
Alexandre J. da Silva ◽  
Vincent Hill
Keyword(s):  
Large Volume ◽  
Wash Water ◽  
Sampling Techniques ◽  
Cyclospora Cayetanensis

Search for Melanoma Markers in Plasma and Serum Samples

2005 ◽  
Vol 11 (3) ◽  
pp. 353-360 ◽  
Author(s):  
Roberta Seraglia ◽  
Susanna Vogliardi ◽  
Graziella Allegri ◽  
Stefano Comai ◽  
Mario Lise ◽  
...  
Keyword(s):  
High Frequency ◽  
Healthy Subjects ◽  
Ionic Species ◽  
Low Molecular Weight ◽  
Ionization Mass ◽  
Plasma Samples ◽  
Serum Samples ◽  
Blood Samples ◽  
Melanoma Patients ◽  
Diagnostic Ions

Fourteen blood samples from patients with melanomas and 11 blood samples from healthy subjects were analyzed by matrix-assisted laser desorption/ionization mass spectrometry. The study focussed on species of low molecular weight, in the 800–5000 Da range, present in plasma and sera. While for healthy subjects plasma samples lead to the production of a higher number of ionic species, for melanoma patients a high number of diagnostic ions, present with high frequency and with quite high relative abundance, are present, in particular, in serum samples and, to a lesser extent, also in plasma. Since plasma samples are obtained more easily in comparison to sera, it is possible to suggest that plasma can also be used for these studies.

scholarly journals Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration

2007 ◽  
Vol 156 (6) ◽  
pp. 647-653 ◽  
Author(s):  
Alexandra Keller ◽  
Zida Wu ◽  
Juergen Kratzsch ◽  
Eberhard Keller ◽  
Werner F Blum ◽  
...  
Keyword(s):  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Open Label ◽  
Igf Binding Proteins ◽  
Trained Subjects ◽  
Routes Of Administration ◽  
Igf Binding ◽  
Serum Gh ◽  
Different Doses ◽  
Igfbp 3

Objective: Pharmacokinetic and pharmacodynamic data after recombinant human GH (rhGH) administration in adults are scarce, but necessary to optimize replacement therapy and to detect doping. We examined pharmacokinetics, pharmacodynamics, and 20 kDa GH after injection of rhGH at different doses and routes of administration. Design: Open-label crossover study with single boluses of rhGH. Methods: Healthy trained subjects (10 males, 10 females) received bolus injections of rhGH on three occasions: 0.033 mg/kg s.c., 0.083 mg/kg s.c., and 0.033 mg/kg i.m. Concentrations of 22 and 20 kDa GH, IGF-I, and IGF-binding proteins (IGFBP)-3 were measured repeatedly before and up to 36 h after injection. Results: Serum GH maximal concentration (Cmax) and area under the time-concentration curve (AUC) were higher after i.m. than s.c. administration of 0.033 mg/kg (Cmax 35.5 and 12.0 μ g/l; AUC 196.2 and 123.8). Cmax and AUC were higher in males than in females (P < 0.01) and pharmacodynamic changes were more pronounced. IGFBP-3 concentrations showed no dose dependency. In response to rhGH administration, 20 kDa GH decreased in females and remained suppressed for 14–18 h (low dose) and 30 h (high dose). In males, 20 kDa GH was undetectable at baseline and throughout the study. Conclusions: After rhGH administration, pharmacokinetic parameters are mainly influenced by route of administration, whereas pharmacodynamic variables and 20 kDa GH concentrations are determined mainly by gender. These differences need to be considered for therapeutic use and for detection of rhGH doping.

scholarly journals Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Ali Mohamed Ali ◽  
Melissa A. Penny ◽  
Thomas A. Smith ◽  
Lesley Workman ◽  
Philip Sasi ◽  
...  
Keyword(s):  
Age Groups ◽  
Parent Drug ◽  
Hemoglobin Concentration ◽  
Pooled Analysis ◽  
Drug Formulation ◽  
Pharmacokinetic Parameters ◽  
Mixed Effects Modeling ◽  
Dosing Regimens ◽  
Disease Effect ◽  
Disposition Model

ABSTRACTAmodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.

The Comparative Pharmacodynamics of Remifentanil and Its Metabolite, GR90291, in a Rat Electroencephalographic Model 

1999 ◽  
Vol 90 (2) ◽  
pp. 535-544 ◽  
Author(s):  
Eugene H. Cox ◽  
Mariska W. E. Langemeijer ◽  
Josy M. Gubbens-Stibbe ◽  
Keith T. Muir ◽  
Meindert Danhof
Keyword(s):  
Steady State ◽  
Time Course ◽  
Parent Drug ◽  
Volume Of Distribution ◽  
Pharmacodynamic Model ◽  
Pharmacokinetic Parameters ◽  
Maximal Effect ◽  
Total Blood ◽  
The Mean

Background The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. Methods Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood. Results Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6). Conclusions Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.

Determination of tissue plasminogen activator and its "fast" inhibitor in plasma.

1986 ◽  
Vol 32 (3) ◽  
pp. 482-485 ◽  
Author(s):  
J Chmielewska ◽  
B Wiman
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasma Samples ◽  
Inhibitor Concentration ◽  
Blood Samples ◽  
Analytical Recovery ◽  
Specific Determination ◽  
Tissue Plasminogen ◽  
Coupled Assay

Abstract We describe efficient, accurate methods for specific determination of tissue plasminogen activator (t-PA, EC 3.4.21.31) and its "fast" inhibitor in plasma. In this coupled assay, a sample containing t-PA is incubated with plasminogen, a plasmin (EC 3.4.21.7) substrate of low Km and high Kcat, and fibrin as a stimulator. The inhibitor of t-PA is determined by incubating the sample with a known amount of t-PA in excess, then determining the residual t-PA. Both t-PA and t-PA inhibitor can be determined in many samples simultaneously within a few hours. These assays are modifications of procedures described by us (Clin Chim Acta 1983;127:279-88 and Thromb Res 1983;31:427-36). Their accuracy as assessed by analytical recovery of pure t-PA added to blood samples (91 +/- 4%) or of partly purified inhibitor added to plasma samples (102 +/- 10%) is satisfactory, as is their precision. For the t-PA assay the CV was 1.6% (within run) or 4.1% (between run). The corresponding values for the inhibitor assay were 4.5% (within run) or 8.4% (between run) if the inhibitor concentration exceeded 3 arb. units/mL.

Stability of 5-fluorouracil in whole blood and plasma.

1987 ◽  
Vol 33 (12) ◽  
pp. 2299-2300 ◽  
Author(s):  
R F Murphy ◽  
F M Balis ◽  
D G Poplack
Keyword(s):  
Whole Blood ◽  
Enzymatic Degradation ◽  
Room Temperature ◽  
Parent Drug ◽  
Plasma Samples ◽  
Blood Specimens ◽  
The Stability ◽  
Frozen Plasma

Abstract We studied the stability of 5-fluorouracil (5-FU) in plasma and whole blood kept at room temperature and on ice for 1 to 24 h. At room temperature, there was a steady loss of 94% of the parent drug over 24 h in whole blood and 52% in plasma. In the presence of an excess of uracil, 5-FU was stable for 24 h, suggesting that the loss of 5-FU is the result of enzymatic degradation. 5-FU is more stable in whole blood and plasma when samples are kept cold. For blood and plasma samples maintained on ice, the loss was only 30% and 10% of the parent drug in the respective samples over 24 h. Frozen plasma samples (-20 degrees C) were stable for five weeks. Blood specimens collected for quantifying 5-FU should be immediately placed on ice, and the plasma should be separated and frozen as promptly as possible.

scholarly journals Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

2004 ◽  
Vol 48 (11) ◽  
pp. 4328-4331 ◽  
Author(s):  
Robert DiCenzo ◽  
Derick Peterson ◽  
Kim Cruttenden ◽  
Gene Morse ◽  
Garret Riggs ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Valproic Acid ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Blood Samples ◽  
Immunodeficiency Virus ◽  
Before And After ◽  
Trough Concentrations ◽  
Hiv 1

ABSTRACT Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C 0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C 0 and 8-h VPA concentrations versus the control (n = 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n = 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

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