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Disposition Kinetics (disposition + kinetics)
Selected AbstractsUptake and Dispersion of Metformin in the Isolated Perfused Rat LiverJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000CHEN-HSI CHOU Although metformin is a widely used oral antihyperglycaemic, the exact mechanisms of its cellular uptake and action remain obscure. In this study the hepatic extraction and disposition kinetics of metformin were investigated by use of an isolated in-situ rat liver preparation. The liver was perfused in single-pass mode with protein-free Krebs bicarbonate medium at a flow rate of 20mLmin,1. During constant infusion with 1 mgL,1 metformin hydrochloride the hepatic uptake of metformin approached equilibrium within 10 min. The steady-state availability, F, determined from the ratio of outflow concentration to input concentration, was 0.99±0.02 (mean±s.d., n=4). The outflow profile of metformin resulting from a bolus injection of 25 ,g into the portal vein, had a sharp peak then a slower declining terminal phase. The mean transit time (MTT; 49.5±14.5, n = 6) and normalized variance (CV2; 4.13±0.05) of the hepatic transit times of metformin were estimated by numerical integration from the statistical moments of the outflow data. The volume of distribution of metformin in the liver (1.58±0.28 mL (g liver),1) was estimated from its MTT. The volume of distribution is greater than the water space of liver, indicating that metformin enters the hepatic aqueous space and becomes distributed among cellular components. The magnitude of CV2 for metformin is greater than for the vascular marker sucrose, suggesting that distribution of metformin into hepatic tissue is not instantaneous. In conclusion, hepatic uptake of metformin is rate-limited by a permeability barrier. Although metformin is accumulated in the liver, the organ does not extract it. [source] Licking induced changes to the pattern of moxidectin milk elimination after topical treatment in dairy cowsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2009F. IMPERIALE Pour-on administration of the macrocyclic lactones anti-parasitic compounds in beef and dairy cattle is now worldwide accepted. However, the information available on their milk excretion pattern, after topical administration is rather limited. Additionally, the cattle licking behaviour has been proven to affect the kinetics of these anti-parasitic compounds. The purpose of this study was to investigate the influence of the natural licking behaviour on the plasma and milk disposition of moxidectin (MXD), topically administered (500 ,g/kg) in lactating dairy cows. Ten lactating Holstein dairy cows (705 kg body weight) were allocated into two experimental groups (n = 5). The licking was prevented during 5 days postadministration in animals in group I, and the remaining cows (group II) were allowed to lick freely. MXD concentrations profiles were measured in plasma and milk over 15 days posttreatment. The licking restriction period caused marked changes in MXD disposition kinetics both in plasma and milk. Both plasma and milk MXD concentrations (partial AUC 0,5 days) were significantly lower (P < 0.05) in licking-restricted cows. After the 5-day of restriction period, the animals were allowed to lick freely, which permitted the oral ingestion of MXD, situation clearly reflected both in plasma profile and milk excretion pattern. Despite the enhanced MXD milk concentrations measured in free-licking cows, drug concentrations did not reach the maximum MXD residues limit. [source] Characterization 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] Comparative disposition kinetics of ofloxacin following a single i.m. and s.c. administration in neonatal calvesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2005A. GAUR First page of article [source] Influence of endotoxin on the disposition kinetics and dosage regimens of oxytetracycline in calvesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2003R. Kumar The influence of endotoxin on the disposition kinetics of oxytetracycline (OTC) (10 mg/kg) was investigated in five healthy ruminating male crossbred calves. The serum concentration-time data of OTC before and after endotoxin challenge were best described by a two-compartment open model. Repeated administration of Escherichia coli endotoxin (1 ,g/kg, i.v.) at an interval of 12 h up to 48 h produced a clear rise in the body temperature and an increase in the pulse and respiration rates. Endotoxin caused a significant reduction in mean transit time in tissue compartment (MTTT) (P , 0.05), mean residence time in the peripheral tissue compartment (MRTT) (P , 0.05), mean residence time in the body (MRTB) (P , 0.05), elimination half-life (t1/2,2) (P , 0.05) and distribution space in tissues (VT) (P , 0.01) and at steady-state (Vd(ss)) (P , 0.01). Endotoxin had no effect on the distribution clearance (ClD), systemic clearance (Cl) and distribution half-life of OTC, while the values of first order rate constant of transfer of drug from tissue to central compartment (K21) and the zero time intercept at terminal phase (C2) were significantly high. The drug dosage regimens to maintain serum OTC concentrations of 0.5, 1, 2, 4, 6 and 8 ,g/mL were also determined in febrile and clinically healthy animals. [source] Plasma achiral and chiral pharmacokinetic behaviour of intravenous oxfendazole co-administered with piperonyl butoxide in sheepJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2002S. SÁNCHEZ Co-administration of piperonyl butoxide (PB) potentiates fenbendazole (FBZ) in small ruminants. The resultant increase in bioavailability of FBZ and its metabolite oxfendazole (OFZ) has important implications for the efficacy of these drugs against benzimidazole (BZD)-resistant strains of Teladorsagia circumcincta. This study evaluated the racemic (achiral) and enantiomeric (chiral) plasma disposition kinetics of OFZ and its metabolites after the co-administration of PB and OFZ in sheep. Six 6,8-month-old, parasite-free, female Dorset sheep (30,40 kg) were used in a two-phase crossover experiment. In phase I, three sheep received 30 mg/kg PB orally, followed by a single intravenous (i.v.) injection of OFZ at 5 mg/kg. The other three animals were treated similarly except that 5 mL of water replaced PB. In phase 2, treatments for the two groups were reversed and were given 14 days after the initiation of phase I. Three analytes OFZ, FBZ and fenbendazole sulphone (FBZSO2) were recovered in plasma up to 48 h post-treatment in both experimental groups. Achiral and chiral pharmacokinetic (PK) profiles for OFZ, after the co-administration of PB, were characterized by a significantly greater area under the concentration,time curve (AUC) and a longer mean residence time (MRT). Chiral OFZ distribution ratios were comparable in both treatment groups. Piperonyl butoxide treatment markedly influenced the plasma PK profiles for FBZ and FBZSO2 following OFZ administration. Production of FBZ was enhanced as reflected by increased (> 60%) AUC, delayed Tmax and a significantly delayed (> 45%) elimination (t˝el). Although AUC values for FBZSO2 were not significantly different between groups, this metabolite was depleted more slowly from plasma (t˝el > 60% and MRT > 42%) following PB treatment. This study demonstrated that PB co-administration is associated with an inhibition of OFZ biotransformation, as evidenced by the significantly higher plasma concentrations of OFZ and FBZ, and this could have important implications in terms of antiparasite therapy against BZD-resistant parasite strains. [source] Enhanced plasma and target tissue availabilities of albendazole and albendazole sulphoxide in fasted calves: evaluation of different fasting intervalsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2000S. SÁNCHEZ The influence of different pre- and post-treatment fasting periods on the plasma availability and disposition kinetics of albendazole (ABZ) and its sulphoxide metabolite (ABZSO) in cattle was investigated. The effect of fasting on the distribution of ABZ and ABZSO to different target tissues/fluids was also characterised. In Experiment I, 35 parasite-free Holstein calves were divided into seven groups according to the following feeding conditions and treated intraruminally with ABZ (10 mg/kg): control group (fed ad libitum), 24 h fasting either prior to (24 h pre-) or post (24 h post-) treatment, 24 h fasting with either 6 (6 h pre+18 h post) or 12 h (12 h pre+12 h post-) of feed restriction prior to treatment, 12 h fasting either prior to (12 h pre-) or post (12 h post) treatment. In Experiment II, calves from the same pool of animals were subjected to a 24 h fasting period prior to the same ABZ treatment and killed (two animals) at either 24, 36 or 48 h post-administration to obtain samples of abomasal/intestinal mucosa and fluid contents, bile and lungs. Plasma (Experiment I) and tissues/fluids (Experiment II) samples were analysed by HPLC. All the fasting periods investigated induced marked changes to the plasma availability and disposition kinetics of the ABZSO metabolite. Enhanced plasma availability between 37 and 118%, delayed peak concentrations and extended mean residence times for ABZSO were observed in fasted compared to fed calves. The changes in plasma kinetics, reflecting an altered quantitative gastrointestinal absorption, were reflected in increased availability of ABZ and ABZSO in the target tissues/fluids of fasted calves. The availabilities of ABZ and ABZSO in the gastrointestinal mucosa and fluids in fasted calves were markedly greater than in those fed ad libitum. [source] Toxico-kinetics, recovery efficiency and microsomal changes following administration of deltamethrin to black Bengal goatsPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 3 2001Sanis Juliet Abstract A study of the toxico-kinetics, recovery percentage from different substrates, cytotoxicity and role of cytochrome P450 and b5 of liver microsome in the metabolism of deltamethrin were carried out in female black Bengal goat. The ALD50 value of deltamethrin in goat by intravenous route lies between 0.2 and 0.6,mg,kg,1. Intravenous disposition kinetics using a dose of 0.2,mg,kg,1 showed that the maximum blood concentration of deltamethrin was recorded at 0.5,min, followed by rapid decline, and a minimum concentration was detected at 6,min after administration. The following values were obtained,:,Vdarea 0.148 (±,0.02) litre,kg,1; t1/2 (,) 0.22 (±,0.02),min; t1/2 (,) 2.17 (±,0.37),min; Kel 1.05 (±,0.24) min,1; AUC 4.30(±,0.45),µg min,ml,1; ClB 0.05 (±,0.006) litre,kg,1 min,1; T,B 1.93 (±,0.58); fc 0.40(±,0.05). After 10,min, liver retained the maximum residue, and heart, adrenal gland, kidney, spleen, fat and brain also held the insecticide; liver, fat, heart and spleen retained residue after 30,min, and bone, liver and fat retained residue after 60,min of intravenous administration. Oral absorption of deltamethrin was poor and inconsistent, and approximately 65% of administered dose was recovered from faeces and gastrointestinal contents. The excretion of deltamethrin through urine was meagre, and only 0.01 and 0.013% of the administered dose was recovered after 3 and 5 days of oral administration respectively. All the tissues retained the residue after 3 days; while fat, rumen, reticulum, omasum, abomasum, large and small intestine and bone retained the residue after 5 days of oral administration; and the percentage recoveries were 1.73 and 0.027 respectively. Deltamethrin reduced the level of cytochrome P450 content of liver microsomal pellet of goat after 5 days of oral administration. Histopathological examination of liver, kidney, heart, spleen brain and lung sections of treated goats did not reveal any pathological changes. © 2001 Society of Chemical Industry [source] HPLC-fluorescence assay for measuring mosapride in small volumes of rat plasmaBIOMEDICAL CHROMATOGRAPHY, Issue 3 2010Ching-Ling Cheng Abstract A simple and sensitive HPLC-fluorescence assay was developed for the determination of a gastroprokinetic agent mosapride in small volumes of rat plasma. Samples (50 ,L) were treated with 200 ,L of the internal standard solution (cisapride, 0.1 ,g/mL in acetonitrile). Chromatographic separation was achieved on a C18 column by gradient elution with the mobile phase of acetonitrile-water containing 20 mM potassium dihydrogen phosphate, at a flow rate of 1 mL/min. Fluorescence was measured with excitation and emission set at 315 and 354 nm, respectively. The retention time was about 16 min for cisapride and 20 min for mosapride. No endogenous substances were found to interfere. The calibration curve was linear from 0.015 to 10 ,g/mL. The lower limit of quantification was 0.015 ,g/mL. The intra- and inter-day precision expressed as relative standard deviation did not exceed 7.7%, and the accuracy was within 4.7% deviation of the nominal concentration. The method was used successfully to investigate the disposition kinetics of mosapride in rats. Copyright © 2009 John Wiley & Sons, Ltd. [source] Comparison of the pharmacokinetics of moxidectin and ivermectin after oral administration to beagle dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2007Sayer I. Al-Azzam Abstract This study compares plasma disposition kinetics of ivermectin and moxidectin after oral administration to beagle dogs experimentally infected with the filarial parasite, Brugia pahangi. Sixteen dogs were selected and randomly allocated into two groups of eight dogs each. Animals in each group received either ivermectin or moxidectin by oral route at a dose of 250 µg/kg. Blood samples were collected from 0.5 h up to 56 days post-treatment and the plasma was analysed by high performance liquid chromatography (HPLC). The obtained data were analysed by compartmental and non-compartmental pharmacokinetic techniques. Peak plasma concentrations (Cmax) of 234.0 ± 64.3 ng/ml (mean ± SD) were obtained for moxidectin and 132.6 ± 43.0 ng/ml for ivermectin. The terminal elimination half-life was significantly (p<0.01) longer in the moxidectin treated group (621.3 ± 149.3 h) than for ivermectin treated group (80.3 ± 29.8 h). A significantly (p< 0.01) larger Vss/F was obtained for moxidectin (19.21 ± 3.61 l/kg) compared with ivermectin (5.35 ± 1.29 l/kg). The mean estimates of CL/F of moxidectin and ivermectin were 0.0220 ± 0.00381 and 0.0498 ± 0.0179 l/h/kg, respectively. The comparative plasma disposition kinetics of ivermectin and moxidectin in dogs is reported for the first time. Copyright © 2007 John Wiley & Sons, Ltd. [source] Erythropoietin production rate in phlebotomy-induced acute anemiaBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2004N.H. Al-Huniti Abstract Objective. To estimate the rate of erythropoietin (EPO) production under physiological, conditions and to examine the regulatory mechanism of EPO production in response to acute phlebotomy-induced anemia. Methods. Six sheep each underwent two phlebotomies in which the hemoglobin (Hb) was reduced to 3,4 g/dl over 4,5 h. The EPO plasma level, reticulocytes, Hb and EPO clearance were followed by frequent blood sampling. The EPO production rate was determined by a semi-parametric method based on a disposition decomposition analysis that accounts for the nonlinear disposition kinetics of EPO and corrects for time-dependent changes in the clearance. Results. The controlled drop in hemoglobin resulted in an abrupt increase in the plasma EPO concentration (peak level 812 ± 40 mU/ml, mean ± CV%) that was followed by a rapid drop 2,4 days after the phlebotomy at a time when the sheep were still anemic (Hb = 4.3 ± 16 g/dl). The EPO production rate at baseline was 43 ± 52 U/day/kg and the amounts of EPO produced over an 8 day period resulting from the first and second phlebotomy were 2927 ± 40 U/kg and 3012 ± 31 U/kg, respectively. Conclusions. The rapid reduction in the EPO plasma level observed 2,4 days following the phlebotomy cannot be explained solely by the increase in EPO clearance but also by a reduction in EPO production. Copyright © 2004 John Wiley & Sons, Ltd. [source] The relationships between half-life (t1/2) and mean residence time (MRT) in the two-compartment open body modelBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2004Eyal Sobol Abstract Rationale. In the one-compartment model following i.v. administration the mean residence time (MRT) of a drug is always greater than its half-life (t1/2). However, following i.v. administration, drug plasma concentration (C) versus time (t) is best described by a two-compartment model or a two exponential equation: C=Ae,,t+Be,,t, where A and B are concentration unit-coefficients and , and , are exponential coefficients. The relationships between t1/2 and MRT in the two-compartment model have not been explored and it is not clear whether in this model too MRT is always greater than t1/2. Methods. In the current paper new equations have been developed that describe the relationships between the terminal t1/2 (or t1/2,) and MRT in the two-compartment model following administration of i.v. bolus, i.v. infusion (zero order input) and oral administration (first order input). Results. A critical value (CV) equals to the quotient of (1,ln2) and (1,,/,) (CV=(1,ln2)/(1,,/,)=0.307/(1,,/,)) has been derived and was compared with the fraction (f1) of drug elimination or AUC (AUC-area under C vs t curve) associated with the first exponential term of the two-compartment equation (f1=A/,/AUC). Following i.v. bolus, CV ranges between a minimal value of 0.307 (1,ln2) and infinity. As long as f1 Comparative disposition of ricobendazole enantiomers after intravenous and subcutaneous administration of a racemic formulation to calvesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2000Carles Cristňfol Abstract The enantioselective disposition kinetics of the benzimidazole anthelmintic, ricobendazole (RBZ), have been characterized after its intravenous (iv) and subcutaneous (sc) administration as a racemic formulation to cattle. The (+) and (,) RBZ enantiomeric forms were recovered in plasma after iv and sc administration of the racemic RBZ formulation, using a chiral phase based HPLC method. A biexponential plasma concentration versus time curve was observed for both RBZ enantiomers following the iv treatment. Total body clearance was higher for (,) RBZ (150.4 mL/h,·,kg) compared with that obtained for the (+) RBZ antipode (78.1 mL/h,·,kg). The elimination half-life of the (,) RBZ enantiomer was shorter (T1/2,: 2.67 h) compared with the (+) enantiomer (T1/2,: 5.41 h). The plasma availability (expressed as AUC) was significantly higher for (+) RBZ compared with that obtained for the (,) antipode following both treatments. The enantiomeric ratio in plasma at T0 was close to unity (50% of each enantiomer); the analysis of the concentration ratios (+) RBZ/(,) RBZ, demonstrated an increase in the proportion of (+) RBZ during the time course of the kinetics after both iv and sc treatments. The results presented herein show the enantioselective disposition kinetics of RBZ in cattle and are a further contribution to the understanding of the kinetic behaviour of these sulphoxide-containing benzimidazole anthelmintics in ruminants. Copyright © 2000 John Wiley & Sons, Ltd. [source] Effects of nicotine on cytochrome P450 2A6 and 2E1 activitiesBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Janne Hukkanen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone. , Nicotine is a useful probe for phenotyping cytochrome P450 2A6 activity and chlorzoxazone is a frequently used probe for CYP2E1 activity. , The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities are unknown. WHAT THIS PAPER ADDS , This study demonstrates that CYP2A6 and CYP2E1 activities are not affected by nicotine dosing. , High-dose nicotine treatment has a low potential of interaction with CYP2A6 and CYP2E1 substrates. , The mechanisms of tobacco smoke-elicited changes in CYP2A6 and CYP2E1 activities are yet to be determined. AIMS Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking. METHODS The study had a single-blind, randomized, crossover two-arm design. Twelve healthy smokers were given two transdermal patches with 42-mg nicotine a day or placebo patches, each for 10 days. The subjects abstained from smoking during the study arms. Oral chlorzoxazone was given on day 7 and deuterium-labelled nicotine-d2 and cotinine-d4 infusion on day 8. RESULTS There was no significant influence of transdermal nicotine administration on pharmacokinetic parameters of nicotine-d2 or on the formation of cotinine-d2. Nicotine decreased the volume of distribution (62.6 vs. 67.7 l, 95% confidence interval of the difference ,9.7, ,0.6, P= 0.047) of infused cotinine-d4. There were no significant differences in disposition kinetics of chlorzoxazone between the treatments. CONCLUSIONS CYP2A6 and CYP2E1 activities are not affected by nicotine. The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities remain unknown. [source]
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