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I.v. Dosing (i.v + dosing)
Selected AbstractsCharacterization of the pharmacokinetic disposition of levofloxacin in stallions after intravenous and intramuscular administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2008A. GOUDAH The target of the present study was to investigate the plasma disposition kinetics of levofloxacin in stallions (n = 6) following a single intravenous (i.v.) bolus or intramuscular (i.m.) injection at a dose rate of 4 mg/kg bwt, using a two-phase crossover design with 15 days as an interval period. Plasma samples were collected at appropriate times during a 48-h administration interval, and were analyzed using a microbiological assay method. The plasma levofloxacin disposition was best fitted to a two-compartment open model after i.v. dosing. The half-lives of distribution and elimination were 0.21 ± 0.13 and 2.58 ± 0.51 h, respectively. The volume of distribution at steady-state was 0.81 ± 0.26 L/kg, the total body clearance (Cltot) was 0.21 ± 0.18 L/h/kg, and the areas under the concentration,time curves (AUCs) were 18.79 ± 4.57 ,g.h/mL. Following i.m. administration, the mean t1/2el and AUC values were 2.94 ± 0.78 h and 17.21 ± 4.36 ,g.h/mL. The bioavailability was high (91.76% ± 12.68%), with a peak plasma mean concentration (Cmax) of 2.85 ± 0.89 ,g/mL attained at 1.56 ± 0.71 h (Tmax). The in vitro protein binding percentage was 27.84%. Calculation of efficacy predictors showed that levofloxacin might have a good therapeutic profile against Gram-negative and Gram-positive bacteria, with an MIC , 0.1 ,g/mL. [source] Pharmacokinetic,pharmacodynamic integration of danofloxacin after intravenous, intramuscular and subcutaneous administration to rabbitsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2007E. FERNÁNDEZ-VARÓN The pharmacokinetics of danofloxacin was studied following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration of 6 mg/kg to healthy rabbits. Danofloxacin concentration were determined by high-performance liquid chromatography assay with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of danofloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The danofloxacin plasma concentration versus time data after i.v. administration could best be described by a two-compartment open model. The disposition of i.m. and subcutaneously administered danofloxacin was best described by a one-compartment model. The terminal half-life for i.v., i.m. and s.c. routes was 4.88, 6.70 and 8.20 h, respectively. Clearance value after i.v. dosing was 0.76 L/kg·h. After i.m. administration, the absolute bioavailability was mean (±SD) 102.34 ± 5.17% and the Cmax was 1.87 mg/L. After s.c. administration, the absolute bioavailability was mean (±SD) 96.44 ± 5.95% and the Cmax was 1.79 mg/L. Danofloxacin shows a favourable pharmacokinetics profile in rabbits reflected by parameters such as a long half-life and a high bioavailability. However, in consideration of the low AUC/MIC indices obtained, its use by i.m. and s.c. route against the S. aureus strains assayed in this study cannot be recommended given the risk for selection of first mutant subpopulations. [source] Matrix effects during analysis of plasma samples by electrospray and atmospheric pressure chemical ionization mass spectrometry: practical approaches to their eliminationRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 17 2003Joachim Schuhmacher Some cases of occurrence of matrix effects (mostly ion suppression) in protein-precipitated plasma samples, and their influence on the validity of plasma concentrations and pharmacokinetic parameters, are discussed. The comparison of matrix effects using either electrospray (TurboIonspray, TISP) or atmospheric pressure chemical ionization (APCI) indicated that APCI is less prone to matrix effects. Nevertheless, TISP is usually the first choice of ionization technique since unknown thermally labile metabolites might be present in the plasma samples causing erroneous results. A high impact of ion suppression on the plasma concentrations after intravenous (i.v.) administration was found, depending on the drug formulation (vehicle). Since ion suppression caused significantly lower plasma concentrations (by a factor of up to 5.5) after i.v. dosing, the area under the curve (AUC) was underestimated and the plasma clearance was consequently erroneously high, with an impact on drug candidate selection. By simple stepwise dilution (e.g. 10-fold and 50-fold) of the supernatant of protein-precipitated plasma samples, including all calibration and quality control samples, the matrix effects were recognized and eliminated. Copyright © 2003 John Wiley & Sons, Ltd. [source] Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2009Holger Fuchs Abstract BI 1356 (INN: linagliptin) is an inhibitor of dipeptidyl peptidase-4 (DPP-4). This study investigated whether saturable binding of BI 1356 to its target DPP-4 occurs in tissues and whether drug accumulation occurs at these sites in vivo. In order to test these hypotheses, the tissue distribution of BI 1356 was determined in wild-type and DPP-4 deficient rats at different dose levels by means of whole body autoradiography and measurement of tissue radioactivity concentrations after single i.v. dosing of [14C]-radio labeled BI 1356. The accumulation behavior of drug-related radioactivity in tissues was further explored in an oral repeat dose study. Tissue levels of [14C]BI 1356 related radioactivity were markedly lower in all investigated tissues of the DPP-4 deficient rats and the difference of the dose-dependent increase of radioactivity tissue levels between both rat strains indicates that tissue distribution at low doses of BI 1356 is dominated by binding of BI 1356 to DPP-4 in tissues. As the binding to DPP-4 is strong but reversible, the tissue binding results in a long terminal half-life in several tissues including plasma. The binding capacity to DPP-4 is, however, limited. In the rat, saturation of DPP-4 binding is suggested at an intravenous dose above 0.01,0.1,mg/kg [14C]BI 1356. As the DPP-4 binding capacity is saturated already at low doses, accumulation of BI 1356 in tissues is unlikely, despite the long persistence of low amounts in the body. Copyright © 2009 John Wiley & Sons, Ltd. [source] Absorption, distribution, metabolism and excretion of YM466, a novel factor Xa inhibitor, in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2004Yuji Mano YM466 is a novel factor Xa inhibitor for the treatment of thrombosis. The absorption, distribution, metabolism and excretion of YM466 were investigated in male Fisher rats after a single oral administration. YM466 was absorbed rapidly from all segments of the gastrointestinal tract except the stomach. After oral dosing, the plasma concentration of 14C-YM466 reached a maximum within 0.5h, and declined rapidly with an elimination half-life of 0.64h. The unchanged YM466 accounted for almost all of its radioactivity, suggesting a minimal metabolism in rats. This was also supported by the finding that no metabolites were observed in bile and urine after oral dosing of 14C-YM466. The distribution of 14C-YM466 in tissue was evaluated and the liver and kidney were the organs with radioactivity concentrations consistently higher than that of plasma. Cumulative biliary and urinary excretion of radioactivity in bile duct-cannulated rats was 29.5% and 7.6%, respectively, indicating prominent excretion into bile after oral dosing. This was consistent with the finding that 76.1% and 25.2% of radioactivity dosed were excreted to faeces and urine, respectively, after i.v. dosing. These results suggest that YM466 was rapidly absorbed and then subjected to biliary excretion with a minimal metabolism after oral dosing to rats. Copyright © 2004 John Wiley & Sons, Ltd. [source] The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamicsACTA NEUROLOGICA SCANDINAVICA, Issue 2000N. H. Greig Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a >50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (>70%) and long-lasting inhibition of AChE was achieved (half-life >8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated >3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly. [source] ADME Investigations of Unnatural Peptides: Distribution of a 14C-Labeled ,,3 -Octaarginine in RatsCHEMISTRY & BIODIVERSITY, Issue 7 2007Markus Weiss Abstract The highly positively charged, cell-penetrating ,,3 -octaarginine has been prepared with a radioactive label by acetylation at the N-terminus with a doubly 14C-labeled acetyl group (14CH314CO). With the radioactive compound, an ADME study (Absorption, Distribution, Metabolism, Excretion) was performed in male rats following an intravenous or oral dose of 1,mg/kg. Sampling was carried out after periods ranging from 5,min to 4,d or 7,d for blood/excretia and quantitative whole-body autoradioluminography (QWBA), respectively. After p.o. dosing, no systemic exposure to peptide-related radioactivity was observed, and the dose was completely excreted in the feces within 24,h suggesting the absence of relevant absorption; less than 3% of the i.v. dose was excreted from the animals within 4,d. Blood levels, after i.v. dosing, dropped within 4,d to less than 2% of Cmax and decreased afterwards only very slowly. No metabolites were observed in the systemic circulation. QWBA Data indicated that the distribution of the acetyl- , -octaarginine-related radioactivity in the organs and tissues shifted over time. Notably, after 7,d, the highest concentration was measured in the lymph nodes, and the largest amount was found in the liver. A comparison with the results of two previous ADME investigations of , -peptides (cf. Table,1) reveals that the distribution of the compounds within the animals is structure-dependent, and that there is a full range from oral availability with rather rapid excretion (of a tetrapeptide) to essentially complete lack of both oral absorption and excretion after i.v. administration (of a highly charged octapeptide). A discussion is presented about the in vivo stability and ,drug-ability' of peptides. In general, , -peptides bearing proteinogenic side chains are compared with peptides consisting entirely of D - , -amino acid residues (the enantiomers of the ,natural' building blocks), and suggestions are made regarding a possible focus of future biomedical investigations with , -peptides. [source] Pharmacokinetic Investigation of a 14C-Labelled ,3/, Tetrapeptide in RatsCHEMISTRY & BIODIVERSITY, Issue 11 2004Hansjörg Wiegand The solid-phase synthesis and an ADME investigation with albino and pigmented male rats of the doubly 14C-labelled ,/, -tetrapeptide derivative Ac- ,3hTyr-(D)Trp- ,3hLys- ,3hThr-lactone (3; Fig.,3) are described. After intravenous (i.v.) and peroral (p.o.) administration of the peptide, its concentration in blood and plasma, its tissue distribution, and the metabolism and the excretion of the peptide were analyzed over a period of up to 7,days post dose. The tetrapeptide in its ring opened form, 5, has a bioavailability of ca. 25%; radioactivity is distributed in the animals in an organ-specific way, and the compound appears to pass the blood-brain barrier to a very small extent, if at all (Tables,1,3 and Figs.,2,6). Excretion (37% renal, 44% fecal, including biliary) of the tetrapeptide 4,days after i.v. administration is almost complete, with only 4.3% remaining in the carcass; 4,days after p.o. administration 97% of the dose has been excreted in the feces. Radiochromatograms taken of plasma (0.5 and 24,h after i.v. dosing) and of urine and feces extracts (0,48,h collected) reveal the presence of lactone 3 and/or the corresponding hydroxy acid 5 with essentially no or very minor other peaks, respectively, representing possible metabolites (Tables,4,6, and Fig.,7 and 8). A comparison with a previous ADME investigation of a , -nonapeptide show that , except for the lack of metabolism , all aspects of exposure, distribution, and elimination are different (structure-specific properties). The investigated tetrapeptide 3 is a potent and highly specific agonist of the somatostatin receptor hsst4, rendering the results described herein promising for diagnostic and therapeutic applications of , -peptides. [source] | |||||||||||||