Pharmacokinetics and Excretion of 14C-Labeled Polyethylene Glycol (60 kDa) in Rats

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1473-1473 ◽  
Author(s):  
Andreas Baumann ◽  
Thomas Schwarz ◽  
Dietrich Seidel ◽  
Frank Hucke ◽  
Wolfram Steinke ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Half Life ◽  
Pediatric Population ◽  
Total Radioactivity ◽  
Total Recovery ◽  
Safety Issues ◽  
Animal Body ◽  
Elimination Half ◽  
Cumulative Excretion ◽  
Single Intravenous Administration

Abstract Introduction: Although there is no evidence for PEG-related safety issues with PEGylated proteins in the clinic, questions relating to the pharmacokinetics including disposition and excretion of PEG are being raised more frequently by health authorities nowadays, particularly for PEGylated proteins used chronically and/or in the pediatric population (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/11/WC500135123.pdf).BAY 94-9027, a B-domain–deleted recombinant FVIII with a 60-kDa branched PEG molecule attached via a maleimide linker to an amino acid using site-specific PEGylation, is in clinical development for acute and prophylactic intravenous treatment of hemophilia A. The objective of this study was to investigate the pharmacokinetics and excretion of radioactivity (unchanged compound and radioactive metabolites) after single intravenous administration of 14C-labeled BAY 1025662 (cysteine linker-[60-kDa] PEG part of BAY 94-9027 with the 14C label covalently integrated in the linker) in male Wistar rats. Methods: The administered dose was 11 mg/kg body weight related to BAY 1025662 (approximated human lifetime dose of PEG 60 kDa resulting from treatment with BAY 94-9027). The concentrations and amounts of radioactivity in urine, feces, blood, plasma, and selected organs and tissues were investigated in order to determine the excretion via urine and feces, and the pharmacokinetics of total radioactivity and radioactive residues in the animal body. Results: After single intravenous administration of 14C-BAY 1025662 to rats, a fast initial elimination of 14C radioactivity was observed; 63.2% of administered radioactivity was excreted within the first 24 hours (51.4% in urine, 11.8% in feces). Up to day 7, 75.6% of administered radioactivity was excreted predominantly via urine. The balance/recovery of radioactivity on day 7 amounted to 99.0% in relation to the administered radioactive dose. The radioactive residue in the animals amounted to 23.4% of administered dose. The majority of the residual radioactivity was recovered in the carcass and skin, followed by liver and kidneys. The excretion of radioactivity continued at steadily decreasing levels until the end of the study. The daily radioactivity excretion decreased from 2.1% at 72 hours to 0.013% of dose at 6 months after administration of 14C-BAY 1025662. The cumulative excretion of radioactivity via urine and feces was calculated (partly interpolated) to 92.2% of the administered radioactive dose by the end of the experiment on day 168 (74.5% via urine, 17.4% via feces, and 0.294% recovered in the cage wash). The radioactivity was continuously albeit slowly eliminated from the investigated organs and tissues. The elimination half-life of radioactivity was 26 and 23 days in blood and plasma, respectively. The corresponding elimination half-lives of radioactivity were 35, 41, and 31 days in the liver, carcass, and skin, respectively. Radioactivity elimination from kidneys was biphasic with a terminal half-life of 92 days. The radioactive residues in the animals excluding the gastrointestinal tract decreased during the study from 22.5% on day 7 to 1.79% of dose at the end of the study on day 168. There was no indication for any retention or irreversible binding of radioactivity in the animal body. The total recovery of radioactivity (cumulative excretion plus residues in the animals) was 94% in relation to the administered dose at the end of the experiment on day 168. Conclusions: In this study, nearly complete excretion of the 60-kDa PEG molecule (measured as total radioactivity) could be observed, with a fast initial elimination in the first few days and a subsequent considerably slower process until the end of the observation period (6 months). These results are in agreement with recently proposed fast and slow processes for the renal excretion of large PEG and PEG proteins (Baumann, A. et al. Drug Discov Today. 2014:[Epub ahead of print, http://dx.doi.org/10.1016/j.drudis.2014.06.002]). Disclosures Baumann: Bayer Pharma AG: Employment. Schwarz:Bayer Pharma AG: Employment. Seidel:Bayer Pharma AG: Employment. Hucke:Bayer Pharma AG: Employment. Steinke:Bayer Pharma AG: Employment. Buehner:Bayer Pharma AG: Employment.

scholarly journals Pharmacokinetics of Pantoprazole and Pantoprazole Sulfone in Goats After Intravenous Administration: A Preliminary Report

2021 ◽  
Vol 8 ◽  
Author(s):  
Joe S. Smith ◽  
Jonathan P. Mochel ◽  
Windy M. Soto-Gonzalez ◽  
Rebecca R. Rahn ◽  
Bryanna N. Fayne ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Half Life ◽  
Plasma Clearance ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Study Objective ◽  
Elimination Half Life ◽  
Elimination Half

Background: Ruminant species are at risk of developing abomasal ulceration, but there is a lack of pharmacokinetic data for anti-ulcer therapies, such as the proton pump inhibitor pantoprazole, in goats.Objective: The primary study objective was to estimate the plasma pharmacokinetic parameters for pantoprazole in adult goats after intravenous administration. A secondary objective was to describe the pharmacokinetic parameters for the metabolite, pantoprazole sulfone, in goats.Methods: Pantoprazole was administered intravenously to six adult goats at a dose of 1 mg/kg. Plasma samples were collected over 36h and analyzed via reverse phase high performance liquid chromatography for determination of pantoprazole and pantoprazole sulfone concentrations. Pharmacokinetic parameters were determined by non-compartmental analysis.Results: Plasma clearance, elimination half-life, and volume of distribution of pantoprazole were estimated at 0.345 mL/kg/min, 0.7 h, and 0.9 L/kg, respectively following IV administration. The maximum concentration, elimination half-life and area under the curve of pantoprazole sulfone were estimated at 0.1 μg/mL, 0.8 h, and 0.2 hr*μg/mL, respectively. The global extraction ratio was estimated 0.00795 ± 0.00138. All animals had normal physical examinations after conclusion of the study.Conclusion: The reported plasma clearance for pantoprazole is lower than reported for foals, calves, and alpacas. The elimination half-life appears to be < that reported for foals and calves. Future pharmacodynamic studies are necessary for determination of the efficacy of pantoprazole on acid suppression in goats.

BIODYNAMICS OF 1.2α-METHYLENE-6-CHLORO-PREGNA-4,6-DIEN-17α-OL-3,20-DIONE (CYPROTERONE) IN MAN FOLLOWING ORAL AND INTRAVENOUS ADMINISTRATION

1970 ◽  
Vol 64 (2) ◽  
pp. 228-252 ◽  
Author(s):  
E. Gerhards ◽  
H. Röpke ◽  
P. E. Schulze ◽  
H. Hitze
Keyword(s):  
Oral Dose ◽  
Oral Administration ◽  
Ethyl Acetate ◽  
Intravenous Administration ◽  
Perchloric Acid ◽  
Half Life ◽  
Analogue Computer ◽  
Elimination Half ◽  
Deep Compartment ◽  
Intravenous And Oral Administration

ABSTRACT The metabolism and pharmacokinetics (biodynamics) of 1,2α-methylene-[14C]-6-chloro-pregna-4,6-dien-17α-ol-3,20-dione (Cyproterone; Cy) have been investigated in man following intravenous and oral administration. The principal metabolite in the plasma following the intravenous and oral administration is 1,2α-methylene-6-chloro-pregna-4,6-diene-17α,20α-diol-3-one (20α-OH-Cy). After a single oral dose of 100 mg Cy, the concentration of unchanged free Cy during the first 24 hours is about 1 μg/100 ml plasma. Of 100 mg Cy administered p. o., only about 40% was absorbed, 60% being eliminated in the faeces. In the urine, 20α-OH-Cy and 1,2α-methylene-6-chloro-androst-4,6-diene-3,17-dione(17-keto-Cy) were isolated and identified as the principal metabolites. About 60% of the radioactivity in the urine, following oral and intravenous administration of [14C]-Cy, is present in the form of watersoluble compounds (conjugates) which cannot be decomposed either with enzymes (β-glucuronidase, sulphatase) or by means of cold or hot acid hydrolysis. Decomposition by solvolysis with perchloric acid in ethyl acetate, however, is quantitative. On the basis of simulation performed with an analogue computer, the elimination half-life of the deep compartments following intravenous or oral administration of Cy would be between 3 and 5 days, on the basis of 14C-activity. 'Oral administration' of 100 mg Cy daily, as simulated on the analogue computer, is cumulative; an equilibrium in the deep compartment being reached only after about 28 days and that in the blood after about 14 days.

Disposition Kinetics of lincomycin following intravenous administration in hypothyroid goats

2019 ◽  
Author(s):  
Meemansha Sharma ◽  
Vinod Kumar Dumka ◽  
Saloni Singla ◽  
Rajdeep Kaur ◽  
Raushan Kumar Singh
Keyword(s):  
Dose Rate ◽  
Intravenous Administration ◽  
Half Life ◽  
Total Body Clearance ◽  
Small Ruminants ◽  
Blood Samples ◽  
Elimination Half ◽  
Total Body ◽  
Kinetics Of ◽  
Body Clearance

Hypothyroidism is a common disorder of small ruminants and is expected to alter the pharmacokinetics of drugs. Hypothyroidism was induced by feeding thiourea at the dose rate 50 mg.kg-1 daily for 28 days to goats. Disposition of lincomycin, after intravenous administration at dose rate 10 mg/kg, was investigated in hypothyroid goats to determine the potential dosage regimen against susceptible microorganisms. Blood samples were collected from 1 min to 24 h of drug administration. The drug was detected in plasma up to 8 h and lincomycin was rapidly distributed from blood to the tissue, as evidenced by the high value of the distribution coefficient (mean ± SEM) 12.3±1.09 h-1. The large Vd (1.78±0.18 L/kg) indicated vast tissue distribution of lincomycin in goats. The elimination half life, AUC and total body clearance were 3.99± 0.25 h, 33.2±1.71 ìg.h/mL and 0.31±0.02 L/h/kg, respectively. Based on results, lincomycin in hypothyroid goats is suggested to be repeated at 12 h interval for organisms sensitive to lincomycin having MIC up to 0.1 µg.ml-1.

ELIMINATION AND METABOLISM OF 6-CHLORO-17α-HYDROXY-16-METHYLENE-4,6-PREGNADIENE-3,20-DIONE ACETATE AND ITS ANALOGUES IN RATS

1971 ◽  
Vol 66 (2) ◽  
pp. 303-316
Author(s):  
Z. Čekan ◽  
O. Horešovský
Keyword(s):  
Half Life ◽  
Isotope Analysis ◽  
Polar Compounds ◽  
Total Radioactivity ◽  
Acetoxy Group ◽  
Total Recovery ◽  
The Individual ◽  
Oral Doses ◽  
Layer Chromatography ◽  
Highly Polar Compounds

ABSTRACT The recovery of radioactivity in the urine, faeces and carcasses following single oral doses of [4-14C] progesterone, 17α-hydroxyprogesterone [2-14C] acetate (14C-AP), 16-methylene-6-dehydro-17α-hydroxyprogesterone [2-14C] acetate (14C-MAP), 6-bromo-16-methylene-6-dehydro17α-hydroxyprogesterone [2-14C] acetate (14C-BrMAP), 6-[36Cl] chloro-16-methylene-6-dehydro-17α-hydroxyprogesterone acetate (36Cl-ClMAP) and 6-chloro-16-methylene-6-dehydro-17α-hydroxyprogesterone [2-14C]-acetate (14C-ClMAP), respectively, was followed during 4–11 days. The total recovery was almost 100 per cent in all the compounds bearing the 17α-[14C] acetoxy group (AP, MAP, ClMAP, BrMAP). Comparison of 14C-ClMAP and 36Cl-ClMAP revealed that about 25 per cent of the administered radioactivity is eliminated in the urine in the form of desacetylated metabolites. However, most of the liberated acetic acid is not exspired, but is probably bound in an unknown form in the organism and excreted in the faeces. The half-life of 36Cl-ClMAP is longer than that of the steroids labelled with 14C in the 17α-acetoxy group (14C-ClMAP, 14C-BrMAP, 14C-MAP, 14C-AP). This fact can be accounted for by a prolonged elimination of desacetylated metabolites. The elimination in the urine of individual compounds was studied with ClMAP, AP, and MAP, the former two compounds being analyzed by double isotope analysis, the last one by single-label technique. The half-life of the individual compounds is shorter than that of the total radioactivity. This indicates that the individual compounds are eliminated faster than most of their metabolites. From the amount of unchanged steroids in the urine (related to the total radioactivity) it is apparent that ClMAP is metabolized less than AP, with MAP probably in an intermediate position. This correlates well with the biological activity of the compounds studied. A preliminary study showed that following the administration of 14C-ClMAP a major portion of the radioactivity was found in both the urine and faeces in a non-conjugated, mostly neutral form. The majority of the neutral metabolites consisted of highly polar compounds. None of the metabolites separated by thin-layer chromatography, however, could be identified.

scholarly journals Pharmacokinetics and skin concentrations of lincomycin after intravenous and oral administration to cats

2013 ◽  
Vol 84 (1) ◽  
Author(s):  
Gabriela A. Albarellos ◽  
Laura Montoya ◽  
Graciela A.A. Denamiel ◽  
Sabrina M. Passini ◽  
María F. Landoni
Keyword(s):  
Plasma Concentration ◽  
Oral Administration ◽  
Intravenous Administration ◽  
Half Life ◽  
Pharmacokinetic Profile ◽  
Maximum Plasma ◽  
Elimination Half Life ◽  
Concentration Time ◽  
Elimination Half ◽  
Intravenous And Oral Administration

The aim of the present study was to describe the plasma pharmacokinetic profile and skin concentrations of lincomycin after intravenous administration of a 15% solution and oral administration of 300 mg tablets at a dosing rate of 15 mg/kg to cats. Susceptibility of staphylococci (n = 31) and streptococci (n = 23) strains isolated from clinical cases was also determined. Lincomycin plasma and skin concentrations were determined by microbiological assay using Kocuria rhizophila ATCC 9341 as test microorganism. Susceptibility was established by the antimicrobial disc diffusion test. Individual lincomycin plasma concentration–time curves were analysed by a non-compartmental approach. After intravenous administration, volume of distribution, body clearance and elimination half-life were 0.97 L/kg ± 0.15 L/kg, 0.17 L/kg ± 0.06 L/h.kg and 4.20 h ± 1.12 h, respectively. After oral administration, peak plasma concentration, time of maximum plasma concentration and bioavailability were 22.52 µg/mL ± 10.97 µg/mL, 0.80 h ± 0.11 h and 81.78% ± 24.05%, respectively. Two hours after lincomycin administration, skin concentrations were 17.26 µg/mL ± 1.32 µg/mL (intravenous) and 16.58 µg/mL ± 0.90 µg/mL (oral). The corresponding skin: plasma ratios were 2.08 ± 0.47 (intravenous) and 1.84 ± 0.97 (oral). The majority of staphylococci and streptococci tested in this study were susceptible to lincosamides (87.09% and 69.56%, respectively). In conclusion, lincomycin administered orally at the assayed dose showed a good pharmacokinetic profile, with a long elimination half-life and effective skin concentration. Therefore, it could be a good first option for treating skin infections in cats.

scholarly journals Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors

2021 ◽  
Vol 14 (2) ◽  
pp. 119
Author(s):  
Ruben A. G. van Eerden ◽  
Esther Oomen-de Hoop ◽  
Aad Noordam ◽  
Ron H. J. Mathijssen ◽  
Stijn L. W. Koolen
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Small Molecule ◽  
Trough Concentration ◽  
Drug Monitoring ◽  
Half Life ◽  
Kinase Inhibitors ◽  
Therapeutic Drug ◽  
Blood Samples ◽  
Elimination Half ◽  
Trough Levels

Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough concentration using the elimination half-life could be a simple and easy way to overcome this problem. In our study plasma concentrations observed during 24 h blood sampling were used for extrapolation to trough levels. The objective was to demonstrate that extrapolation of randomly taken blood samples will lead to equivalent estimated trough samples compared to measured Cmin values. In total 2241 blood samples were analyzed. The estimated Ctrough levels of afatinib and sunitinib fulfilled the equivalence criteria if the samples were drawn after Tmax. The calculated Ctrough levels of erlotinib, imatinib and sorafenib met the equivalence criteria if they were taken, respectively, 12 h, 3 h and 10 h after drug intake. For regorafenib extrapolation was not feasible. In conclusion, extrapolation of randomly taken drug concentrations to a trough concentration using the mean elimination half-life is feasible for multiple SMKIs. Therefore, this simple method could positively contribute to the implementation of TDM in oncology.

scholarly journals 0004 TS-142: A Novel and Potent Dual Orexin Receptor Antagonist with Sleep-Promoting Effects in Rats

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A2-A2
Author(s):  
D Kambe ◽  
H Hikichi ◽  
Y Tokumaru ◽  
M Ohmichi ◽  
Y Konno ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Half Life ◽  
Sleep Onset ◽  
Sleep Time ◽  
Sleep Onset Latency ◽  
Orexin A ◽  
Pharmacokinetic Profiles ◽  
Orexin Receptors ◽  
Elimination Half ◽  
Emg Electrodes

Abstract Introduction The orexin system plays a pivotal role in regulating sleep and wakefulness, thus, orexin receptors (OX1 and OX2 receptors) have gained much attention as promising therapeutic targets for the treatment of insomnia. We synthesized a novel and potent dual orexin receptor antagonist (DORA), ORN0829 (investigation code name as TS-142), which was designed to have short-acting effects. Here we report pharmacological and pharmacokinetic profiles of ORN0829 in rats. Methods The antagonistic activities of ORN0829 were assessed using calcium mobilization assays. Ala-orexin A-induced [Ca2+]i response was measured with CHO-K1 cells stably expressing human/rat orexin receptor. Rats implanted the EEG/EMG electrodes were orally administrated ORN0829 at doses of 1, 3 or 10 mg/kg at the dark onset and sleep-wake stages were inspected visually. In addition, pharmacokinetic profiles of ORN0829 were investigated in rats. Results ORN0829 inhibited Ala-orexin A-increased [Ca2+]i response with a Kb of 0.67/0.44 nmol/L (for human/rat OX1 receptor), and with a Kb of 0.84/0.80 nmol/L (for human/rat OX2 receptor), respectively, indicating that ORN0829 is a potent DORA with no species differences. ORN0829 dose-dependently increased total sleep time and reduced sleep onset latency at doses of 1, 3 and 10 mg/kg. Importantly, the ORN0829 levels in plasma and cerebrospinal fluid rapidly reached a maximum concentration, and decreased with an elimination half-life of less than 1 h. Conclusion The present study indicates that ORN0829 is a novel and potent DORA with sleep-promoting effects, and that it exhibits ideal pharmacokinetic profiles (rapid absorption and short half-life) in rats. A phase 2a study of TS-142 using patients with insomnia has been completed, which is presented in a separate poster. Support Taisho Pharmaceutical. Co., Ltd.

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