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Distribution Volume (distribution + volume)
Selected AbstractsPopulation pharmacokinetics of imipenem in burn patientsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2003Eric Dailly Abstract The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a population pharmacokinetic approach, and (ii) to test the influence of factors on pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n = 47, 118 samples) and analysed by a nonlinear mixed effect modelling method. Among the tested covariates (age, gender, body weight, height, size of burn and creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic parameters substantially. The best fit is obtained with a two-compartment model integrating a linear,inverse relationship between imipenem clearance and creatinine plasma level. The estimates of imipenem clearance (16.37 ± 0.204 L/h) and of the distribution volume of the central compartment (0.376 ± 0.039 L/kg) are higher in the population of burn patients than the estimates in healthy subjects. This result is connected with high values of glomerule filtration rate and confirms the interest of therapeutic drug monitoring of imipenem in burn patients and particularly for patients with extreme values of creatinine clearance. [source] Repeatability of measurements of the initial distribution volume of glucose in haemodynamically stable patientsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2004B. O. Rose MD Summary Aims:, The initial distribution volume of glucose (IDVG) has been proposed to provide a useful tool to estimate the central extracellular fluid volume. The purpose of this study was to determine the repetition interval of two consecutive measurements in haemodynamically stable patients without presence of recent changes in fluid status. Methods:, Twenty-nine patients admitted to the general intensive care unit of the University of Hirosaki Hospital were entered into this study. After achieving a haemodynamically stable state in each patient regardless of an infusion of vasoactive drugs, two glucose challenges at an interval of either 30 or 60 min, were carried out to calculate the IDVG. The IDVG was calculated using a one-compartment model after intravenous administration of glucose (5 g) followed by serial arterial blood sampling. Results:, Although plasma glucose levels immediately before the second glucose challenge in either group were increased compared with those of the first challenge (P < 0·001, respectively), the bias of the IDVG measurements was 0·08 ± 0·32 L (SD) for the 30-min group and ,0·19 ± 0·28 L for the 60-min group. Conclusions:, Our results indicate that IDVG determinations can be reliably repeated within a minimum interval of 30 min. [source] Ab initio computational study of positron emission tomography ligands interacting with lipid molecule for the prediction of nonspecific bindingJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 14 2008Lula Rosso Abstract Nonspecific binding is a poorly understood biological phenomenon of relevance in the study of small molecules interactions in vivo and in drug development. Nonspecific binding is thought to be correlated in part to a molecule's lipophilicity, typically estimated by measuring (or calculating) octanol,water partition coefficient. This is, however, a gross simplification of a complex phenomenon. In this article, we present a computational method whose aim is to help identify positron emission tomography (PET) ligands with low nonspecific binding characteristics by investigating the molecular basis of ligand,membrane interaction. We considered a set consisting of 10 well-studied central nervous system PET radiotracers acting on a variety of molecular targets. Quantum mechanical calculations were used to estimate the strength of the interaction between each drug molecule and one phospholipid molecule commonly present in mammalian membranes. The results indicate a correlation between the computed drug,lipid interaction energy and the in vivo nonspecific distribution volume relative to the free tracer plasma concentration, calculated using standard compartmental modeling for the analysis of PET data. Significantly, the drugs whose interaction with the lipid molecule more favorably possessed, in general, a higher nonspecific binding value, whereas for the drugs taken in consideration in this study, the water-octanol partition coefficient, log P, did not show good predictive power of the nonspecific binding. This study also illustrates how ab initio chemical methods may offer meaningful and unbiased insights for the understanding of the underlying chemical mechanisms in biological systems. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Tissue edema does not change gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced T1 relaxation times of viable myocardium,,JOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 6 2005Gang Li MD Abstract Purpose To determine whether tissue edema changes gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced T1 relaxation times of the viable myocardium. Materials and Methods A total of 16 isolated pig hearts were divided into four groups (N = 4/group) and perfused in a Langendorff apparatus. Gd-DTPA was injected into the aortic perfusion line. Tissue edema was then induced by two hours of simultaneous arterial/venous perfusion (SAVP). Myocardial water content and T1 relaxation times were monitored throughout SAVP. The volumes of the extracellular and intracellular compartments were assessed using 31P MRS-detectable markers, phenylphosphonic acid (PPA) and dimethyl methylphosphonate (DMMP). Results Tissue water content in both viable and infarcted myocardium increased significantly during two-hour SAVP. However, Gd-DTPA-enhanced T1 relaxation times of the viable myocardium remained relatively unchanged. Infarcted myocardium, on the other hand, exhibited significant T1 shortening during SAVP. Furthermore, SAVP resulted in significant expansions of both extracellular and intracellular compartments, but the ratio of the volumes of the two compartments remained relatively constant. Conclusion Tissue edema in the viable myocardium does not increase the relative distribution volume of the contrast agent. As a result, edema does not change Gd-DTPA-enhanced T1 relaxation times of the viable myocardium. J. Magn. Reson. Imaging 2005;21:744,751. Published 2005 Wiley-Liss, Inc. [source] Cerebral kinetics of oxycodone in conscious sheepJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2006Hanne H. Villesen Abstract Oxycodone is an opioid analgesic that is administered orally or parenterally. The time-course of opioid action is a function of the systemic kinetics of the opioid, and the rate and extent of its entry into the brain and central nervous system. The latter is incompletely understood for oxycodone. Therefore, the cerebral kinetics of oxycodone was quantified using a conscious chronically instrumented sheep preparation. Five sheep were administered oxycodone as intravenous infusions (30 mg over 4 min). Using hybrid physiologically based kinetic models, cerebral kinetics was estimated from arterio-sagittal sinus concentration gradients and cerebral blood flow (CBF). A two-compartment membrane-limited model best described the data. The volume of the first brain compartment was 35.4 mL with a half-life of equilibrium of 0.6 min. The brain:blood equilibration of oxycodone was relatively slow (half-life of 7.2 min), with a large deep cerebral distribution volume (222.8 mL) for the second compartment and a moderate membrane permeability of 54.8 mL/min, which exceeded the nominal CBF (40 mL/min). Drug retention in the brain was 1.3% after 45 min. In conclusion, pharmacokinetic modelling of oxycodone showed a delayed equilibration between brain and blood of a nature that would be affected by changes in both CBF and blood brain barrier permeability. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1666,1676, 2006 [source] In vivo pharmacology and antidiarrheal efficacy of a thiazolidinone CFTR inhibitor in rodentsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2005N.D. Sonawane Abstract A small-molecule inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR), 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTRinh -172), reduces enterotoxin-induced intestinal fluid secretion in rodents. Here, we study CFTRinh -172 pharmacology and antidiarrheal efficacy in rodents using 14C-labeled CFTRinh -172, liquid chromatography/mass spectrometry, and a closed intestinal loop model of fluid secretion. CFTRinh -172 was cleared primarily by renal glomerular filtration without chemical modification. CFTRinh -172 accumulated in liver within 5 min after intravenous infusion in mice, and was concentrated fivefold in bile over blood. At 30,240 min, CFTRinh -172 was found mainly in liver, intestine, and kidney, with little detectable in the brain, heart, skeletal muscle, or lung. Pharmacokinetic analysis in rats following intravenous bolus infusion showed a distribution volume of 770 mL with redistribution and elimination half-times of 0.14 h and 10.3 h, respectively. CFTRinh -172 was stable in hepatic microsomes. Closed-loop studies in mice indicated that a single intraperitoneal injection of 20 ,g CFTRinh -172 inhibited fluid accumulation at 6 h after cholera toxin by >90% in duodenum and jejunum, ,60% in ileum and <10% in colon. No toxicity was seen after high-dose CFTRinh -172 administration (3 mg/kg/day in two daily doses) in mice over the first 6 weeks of life. The metabolic stability, enterohepatic recirculation, slow renal elimination, and intestinal accumulation of CFTRinh -172 account for its efficacy as an antidiarrheal. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:134,143, 2005 [source] Capillarization of the sinusoids in liver fibrosis: Noninvasive assessment with contrast-enhanced MRI in the rabbitMAGNETIC RESONANCE IN MEDICINE, Issue 4 2003Bernard E. Van Beers Abstract Sinusoidal capillarization induces microcirculatory changes in liver cirrhosis and fibrosis. The purpose of this study was to assess whether contrast-enhanced MRI can be used to demonstrate the effects of sinusoidal capillarization in liver fibrosis. Dynamic MRI after injection of a low-molecular-weight contrast agent of 0.56 kDa (Gd-DOTA), and two high-molecular-weight contrast agents of 6.47 kDa and 52 kDa (P792 and P717) was performed in rabbits with liver fibrosis induced by cholesterol and diethylstilbestrol. The hepatic distribution volume accessible to the high-molecular-weight agents decreased in the rabbits with liver fibrosis (P792: 7.8% ± 1.7% vs. 10.1% ± 1.8% in normal rabbits, P = .038; P717: 6.2% ± 2.1% vs. 9.7% ± 1.6% in normal rabbits, P = .007), whereas the hepatic mean transit time (MTT) of the low-molecular-weight agent was increased (15.9 ± 8.0 s vs. 8.8 ± 2.6 s in normal rabbits, P = .015). In rabbits with liver fibrosis, the clearance of indocyanine green (ICG) was correlated with the volume accessible to the high-molecular-weight agents (P792: r = 0.810, P = .015; P717: r = 0.857, P = .007). The collagen content of the liver was inversely correlated with the distribution volume of P717 (r = ,.833, P = .010) and with the ICG clearance (r = ,.810, P = .015). It was concluded that the microcirculatory changes induced by sinusoidal capillarization in liver fibrosis can be demonstrated noninvasively with MRI. Magn Reson Med 49:692,699, 2003. © 2003 Wiley-Liss, Inc. [source] Evidence for shutter-speed variation in CR bolus-tracking studies of human pathologyNMR IN BIOMEDICINE, Issue 3 2005Thomas E. Yankeelov Abstract The standard pharmacokinetic model for the analysis of MRI contrast reagent (CR) bolus-tracking (B-T) data assumes that the mean intracellular water molecule lifetime (,i) is effectively zero. This assertion is inconsistent with a considerable body of physiological measurements. Furthermore, theory and simulation show the B-T time-course shape to be very sensitive to the ,i magnitude in the physiological range (hundreds of milliseconds to several seconds). Consequently, this standard model aspect can cause significant underestimations (factors of 2 or 3) of the two parameters usually determined: Ktrans, the vascular wall CR transfer rate constant, and ve, the CR distribution volume (the extracellular, extravascular space fraction). Analyses of animal model data confirmed two predicted behaviors indicative of this standard model inadequacy: (1) a specific temporal pattern for the mismatch between the best-fitted curve and data; and (2) an inverse dependence of the curve's Ktrans and ve magnitudes on the CR dose. These parameters should be CR dose-independent. The most parsimonious analysis allowing for realistic ,i values is the ,shutter-speed' model. Its application to the experimental animal data essentially eliminated the two standard model signature inadequacies. This paper reports the first survey for the extent of this ,shutter-speed effect' in human data. Retrospective analyses are made of clinical data chosen from a range of pathology (the active multiple sclerosis lesion, the invasive ductal carcinoma breast tumor, and osteosarcoma in the leg) that provides a wide variation, particularly of Ktrans. The signature temporal mismatch of the standard model is observed in all cases, and is essentially eliminated by use of the shutter-speed model. Pixel-by-pixel maps show that parameter values from the shutter-speed analysis are increased by more than a factor of 3 for some lesion regions. This endows the lesions with very high contrast, and reveals heterogeneities that are often not seen in the standard model maps. Normal muscle regions in the leg allow validation of the shutter-speed model Ktrans, ve, and ,i magnitudes, by comparison with results of previous careful rat leg studies not possible for human subjects. Copyright © 2004 John Wiley & Sons, Ltd. [source] Widespread decrease of nicotinic acetylcholine receptors in Parkinson's diseaseANNALS OF NEUROLOGY, Issue 1 2006Masahiro Fujita MD Objective Nicotinic acetylcholine receptors have close interactions with the dopaminergic system and play critical roles in cognitive function. The purpose of this study was to compare these receptors between living PD patients and healthy subjects. Methods Nicotinic acetylcholine receptors were imaged in 10 nondemented Parkinson's disease patients and 15 age-matched healthy subjects using a single-photon emission computed tomography ligand [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine. Using an arterial input function, we measured the total distribution volume (V; specific plus nondisplaceable), as well as the delivery (K1). Results Parkinson's disease showed a widespread significant decrease (approximately 10%) of V in both cortical and subcortical regions without a significant change in K1. Interpretation These results indicate the importance of extending the study to demented patients. Ann Neurol 2006;59:174,177 [source] Simultaneous determination of amantadine and rimantadine by HPLC in rat plasma with pre-column derivatization and fluorescence detection for pharmacokinetic studiesBIOMEDICAL CHROMATOGRAPHY, Issue 9 2005Yasuhiko Higashi Abstract We investigated simultaneous high-performance liquid chromatographic (HPLC) determination of amantadine hydrochloride (AMA) and rimantadine hydrochloride (RIM) levels in rat plasma after fluorescent derivatization with o -phthalaldehyde and 2-mercaptoethanol. Afterwards, the method was applied to determine their pharmacokinetics. The retention times of AMA and RIM derivatives were 12.6 and 22.2 min and the lower limits of detection were 0.025 and 0.016 µg[sol ]mL, respectively. The coefficients of variation for intra- and inter-day assay of AMA and RIM were less than 5.1 and 7.6%, respectively. After i.v. administration of AMA or RIM to rats, the total body clearance and distribution volume at the steady-state of RIM were higher than those of AMA. Bioavailability of AMA and RIM was 34.9 and 37.2%, respectively. When AMA and RIM were p.o. co-administered, the area under the plasma concentration,time curve of RIM was significantly lower than that after RIM alone. On the other hand, pharmacokinetic parameters of AMA did not significantly change. These results indicate that our HPLC assay is simple, rapid, sensitive and reproducible for simultaneously determining AMA and RIM concentrations in rat plasma and is applicable to their pharmacokinetic studies. Also, co-administration of AMA and RIM may result in the lack of pharmacological effects of RIM. Copyright © 2005 John Wiley & Sons, Ltd. [source] Pharmacokinetics and allometric scaling of levormeloxifene, a selective oestrogen receptor modulatorBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2003O. Østerberg Abstract The pharmacokinetics of a new selective oestrogen receptor modulator levormeloxifene was investigated in mice, rats, cynomolgus monkeys and humans by compartmental pharmacokinetics. Levormeloxifene was administered as an oral solution in all studies. Allometric scaling was used to predict human pharmacokinetic parameters and the performance of the approach was evaluated. Mean values of clearance confounded by F(CL/F) were 0.073, 0.29, 3.18 and 2.4 l/h in mice, rats, monkeys and humans, respectively. Values of distribution volume at steady state confounded by F(Vss/F) were 0.073 and 7.5 l in mice and rats. In monkeys, values of the central volume F(Vc/F) and volume at steady state F(Vss/F) were 28.9 and 57.9 l, respectively. In humans, values of Vc/F and Vss/F were 106 and 587 l, respectively. Predicted CL/F and Vss/F showed a linear relationship when plotted vs BW on a log,log scale; for CL/F, r was 0.95,0.98 and for Vss/F, r was 0.99. Using allometric scaling the predicted human Vss/F deviated 3-fold from the experimentally determined values. Observed values of CL/F deviated 21,25 fold from the predicted, the latter depending on the scaling method. Confidence intervals for the predicted parameters showed major lack of precision for all the allometric scaling methods. Copyright © 2003 John Wiley & Sons, Ltd. [source] Influence of dose on the distribution kinetics of ciprofloxacin and ofloxacin in the isolated hindlimb of the ratBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2000A.C. Casquero-Dorado Abstract The aim of this study was to determine whether the dose influences the distribution kinetics of ciprofloxacin and ofloxacin in muscle- bone- and skin-tissues included in the isolated hindlimb of the rat. Experiments were carried out in the isolated perfused hindlimb of the rat, administering a single dose of 45, 450 or 900 µg of each quinolone as a bolus injection. Outflow perfusate samples were collected for 20 min and drug levels were determined by an HPLC technique. The mean transit time (MTT) and the distribution volume of ciprofloxacin significantly increased with the dose injected (MTT=1.47±0.69, 8.74±0.27 and 9.52±2.95 min for 45, 450 and 900 µg, respectively). A similar situation was observed with ofloxacin, although the increase in these parameters was less pronounced (MTT=3.65±0.86, 7.92±2.03 and 8.32±1.70 min for 45, 450 and 900 µg, respectively). The distribution of ciprofloxacin and ofloxacin in the rat hindlimb appears to be a dose-dependent process, at least for the dose range considered in this study. This might explain the high variability in the distribution coefficients reported for these drugs in literature. Copyright © 2000 John Wiley & Sons, Ltd. [source] Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2008Jung-Ryul Kim WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Almost all reported studies have investigated the pharmacokinetics of aripiprazole in healthy volunteers. , The pharmacokinetics of dehydroaripiprazole have not been identified in a combined model with aripiprazole. WHAT THIS STUDY ADDS , The data on aripiprazole and dehydroaripiprazole in psychiatric patients were modelled jointly using a population approach. , The apparent clearance of aripiprazole in cytochrome P450 (CYP) 2D6 intermediate metabolizers (IM) was approximately 60% of that in CYP2D6 extensive metabolizers (EM) having two functional alleles, but the exposure to dehydroaripiprazole in CYP2D6 IM was similar to that in EM. AIMS The aims of this study were to develop a combined population pharmacokinetic model for both aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients and to identify to what extent the genetic polymorphisms of cytochrome P450 (CYP) enzymes contribute to the variability in pharmacokinetics (PK). METHODS A population pharmacokinetic analysis was performed using NONMEM software based on 141 plasma concentrations at steady state from 80 patients receiving multiple oral doses of aripiprazole (10,30 mg day,1). RESULTS A one-compartment model with first-order kinetics for aripiprazole and dehydroaripiprazole each was developed to describe simultaneously the concentration data. The absorption rate constant was fixed to 1.06 h,1. The typical value of apparent distribution volume of aripiprazole was estimated to be 192 l. Covariate analysis showed that CYP2D6 genetic polymorphisms significantly influenced the apparent clearance of aripiprazole (CL/F), reducing the interindividual variability on CL/F from 37.8% CV (coefficient of variation) to 30.5%. The CL/F in the CYP2D6 IMs was approximately 60% of that in CYP2D6 EMs having two functional alleles. Based on the CYP2D6 genotype, the metabolic ratios were calculated at 0.20,0.34. However, the plasma concentration : dose ratios of dehydroaripiprazole were not different across the CYP2D6 genotype. CONCLUSIONS This population pharmacokinetic model provided an adequate fit to the data for both aripiprazole and dehydroaripiprazole in psychiatric patients. The usefulness of CYP genotyping as an aid to select the starting dose should be further investigated. [source] Age-related differences in the pharmacokinetics of stavudine in 272 children from birth to 16 years: a population analysisBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2007V. Jullien Aims To develop a population pharmacokinetic model for stavudine in children and to investigate the consistency of the currently recommended dose based on adult target concentrations. Methods The pharmacokinetics of stavudine were investigated using a population approach. Individual estimates of CL/F were used to calculate the stavudine dose required to achieve the area under the concentration-time curve reported in adults given recommended doses. Results Stavudine pharmacokinetics were well described by a one-compartment model with zero-order absorption. Typical population estimates (% interindividual variability) of the apparent distribution volume (V/F) and plasma clearance (CL/F) were 40.9 l (32%) and 16.5 l h,1 (38%), respectively. Stavudine V/F and CL/F were similarly related to age. Mean calculated doses (0.61 mg kg,1 for children less than 2 weeks, 1.23 mg kg,1 for children more than 2 weeks with bodyweight less than 30 kg, and 31.5 mg for children with a bodyweight between 30 and 60 kg) were in agreement with the current paediatric doses (0.5 mg kg,1, 1 mg kg,1, and 30 mg, respectively). Conclusions Our findings support the current recommended paediatric dosage regimens for stavudine, as they result in the same exposure to the drug as in adults. [source] Stereoselective pharmacokinetics of RS-8359, a selective and reversible MAO-A inhibitor, by species-dependent drug-metabolizing enzymesCHIRALITY, Issue 3 2005Wataru Takasaki Abstract RS-8359, (±)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H -cyclopenta[d]pyrimidine selectively and reversibly inhibits monoamine oxidase A (MAO-A). After oral administration of rac -RS-8359 to rats, mice, dogs, monkeys, and humans, plasma concentrations of the (R)-enantiomer were greatly higher than were those of the (S)-enantiomer in all species studied. The AUC(R) to AUC(S) ratios were 2.6 in rats, 3.8 in mice, 31 in dogs, and 238 in monkeys, and the (S)-enantiomer was almost negligible in human plasma. After intravenous administration of RS-8359 enantiomers to rats, the pharmacokinetic parameters showed that the (S)-enantiomer had a 2.7-fold greater total clearance (CLt) and a 70% shorter half-life (t1/2) than those for the (R)-enantiomer but had no difference in distribution volume (Vd). No significant difference in the intestinal absorption rate was observed. The principal metabolites were the 2-keto form, possibly produced by aldehyde oxidase, the cis -diol form, and the 2-keto- cis -diol form produced by cytochrome P450 in rats, the cis -diol form in mice, RS-8359 glucuronide in dogs, and the 2-keto form in monkeys and humans. Thus, the rapid disappearance of the (S)-enantiomer from the plasma was thought to be due to the rapid metabolism of the (S)-enantiomer by different drug-metabolizing enzymes, depending on species. Chirality 17:135,141, 2005. © 2005 Wiley-Liss, Inc. [source] Blood flow rate measurements with indicator techniques revisitedCLINICAL PHYSIOLOGY AND FUNCTIONAL IMAGING, Issue 6 2009Per Sejrsen Summary In view of the emerging role, disturbances in regional blood flow rate seem to play in the pathogenesis of the metabolic syndrome; we review the concepts of the classical indicator dilution and washout techniques used for determinations of regional blood flow rate. Prerequisites, assumptions, necessary precautions for the application of these experimental techniques are emphasized. Special attention has been carried out to elucidate the consequence of a choice of indicators having a large distribution volume in the tissues. [source] Pharmacokinetics of difloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applicationsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2008H. Z. DING Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t1/2,) were 17.14 ± 4.14, 25.79 ± 8.10, 16.67 ± 4.04 (pigs) and 6.11 ± 1.50, 5.64 ± 0.74, 8.20 ± 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (Cmax) of 1.77 ± 0.66, 2.29 ± 0.85 (pigs) and 2.51 ± 0.36, 1.00 ± 0.21 ,g/mL (broilers) attained at tmax of 1.29 ± 0.26, 1.41 ± 0.88 (pigs) and 0.86 ± 0.4, 4.34 ± 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 ± 28.9)% and (105.7 ± 37.1)% (pigs) and (77.0 ± 11.8)% and (54.2 ± 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(Vd(area)) of 4.91 ± 1.88 and 3.10 ± 0.67 L/kg and total body clearances(ClB) of 0.20 ± 0.06 and 0.37 ± 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t1/2ka, t1/2,) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 ,g/mL and <0.1 ,g/mL respectively. [source] Pharmacokinetics of sarafloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applicationsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2001H. Z. Ding Pharmacokinetics of sarafloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of 5 (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analysed by a noncompartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t1/2,) were 3.37 ± 0.46, 4.66 ± 1.34, 7.20 ± 1.92 (pigs) and 2.53 ± 0.82, 6.81 ± 2.04, 3.89 ± 1.19 h (broilers), respectively. After i.m. and p.o. doses, bioavailabilities (F) were 81.8 ± 9.8 and 42.6 ± 8.2% (pigs) and 72.1 ± 8.1 and 59.6 ± 13.8% (broilers), respectively. Steady-state distribution volumes (Vd(ss)) of 1.92 ± 0.27 and 3.40 ± 1.26 L/kg and total body clearances (ClB) of 0.51 ± 0.03 and 1.20 ± 0.20 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), mean residence times (MRT), and mean absorption times (MAT) were also determined. Sarafloxacin was demonstrated to be more rapidly absorbed, more extensively distributed, and more quickly eliminated in broilers than in pigs. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 10 mg/kg given intramuscularly every 12 h in pigs, or administered orally every 8 h in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 ,g/mL. [source] The MRI-measured arterial input function resulting from a bolus injection of Gd-DTPA in a rat model of stroke slightly underestimates that of Gd-[14C]DTPA and marginally overestimates the blood-to-brain influx rate constant determined by Patlak plotsMAGNETIC RESONANCE IN MEDICINE, Issue 6 2010Tavarekere N. Nagaraja Abstract The hypothesis that the arterial input function (AIF) of gadolinium-diethylenetriaminepentaacetic acid injected by intravenous bolus and measured by the change in the T1 -relaxation rate (,R1; R1 = 1/T1) of superior sagittal sinus blood (AIF-I) approximates the AIF of 14C-labeled gadolinium-diethylenetriaminepentaacetic acid measured in arterial blood (reference AIF) was tested in a rat stroke model (n = 13). Contrary to the hypothesis, the initial part of the ,R1 -time curve was underestimated, and the area under the normalized curve for AIF-I was about 15% lower than that for the reference AIF. Hypothetical AIFs for gadolinium-diethylenetriaminepentaacetic acid were derived from the reference AIF values and averaged to obtain a cohort-averaged AIF. Influx rate constants (Ki) and proton distribution volumes at zero time (Vp + Vo) were estimated with Patlak plots of AIF-I, hypothetical AIFs, and cohort-averaged AIFs and tissue ,R1 data. For the regions of interest, the Kis estimated with AIF-I were slightly but not significantly higher than those obtained with hypothetical AIFs and cohort-averaged AIF. In contrast, Vp + Vo was significantly higher when calculated with AIF-I. Similar estimates of Ki and Vp + Vo were obtained with hypothetical AIFs and cohort-averaged AIF. In summary, AIF-I underestimated the reference AIF; this shortcoming had little effect on the Ki calculated by Patlak plot but produced a significant overestimation of Vp + Vo. Magn Reson Med 63:1502,1509, 2010. © 2010 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||