Kinetics of dodecanedioic acid triglyceride in rats

1999 ◽  
Vol 276 (3) ◽  
pp. E497-E502
Author(s):  
A. de Gaetano ◽  
G. Mingrone ◽  
M. Castagneto ◽  
G. Benedetti ◽  
A. V. Greco ◽  
...  
Keyword(s):  
High Performance ◽  
Compartment Model ◽  
High Performance Liquid Chromatographic ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Parameter Estimates ◽  
Tissue Uptake ◽  
Male Wistar Rats ◽  
Dodecanedioic Acid ◽  
Kinetics Of

The kinetics of the triglyceride of dodecanedioic acid (TGDA) has been investigated in 30 male Wistar rats after a rapid intravenous bolus injection. TGDA and its product of hydrolysis, nonesterified dodecanedioic acid (NEDA), were measured in plasma samples taken at different times using an improved high-performance liquid chromatographic method. The 24-h urinary excretion of TGDA was 1.54 ± 0.37 μmol, corresponding to ∼0.67% of the administered amount. Several kinetics models were considered, including central and peripheral compartments for the triglyceride and the free forms and expressing transports between compartments with combinations of linear, carrier-limited, or time-varying mechanisms. The parameter estimates of the kinetics of TGDA and of NEDA were finally obtained using a three-compartment model in which the transfer of TGDA to NEDA was assumed to be linear, through a peripheral compartment, and the tissue uptake of NEDA was assumed to be carrier limited. TGDA had a large volume of distribution (∼0.5 l/kg body wt) with a fast disappearance rate from plasma (0.42 min−1), whereas NEDA had a very small volume of distribution (∼0.04 l/kg body wt) and a tissue uptake with maximal transport rate of 0.636 mM/min. In conclusion, this first study on the triglyceride form of dodecanedioic acid indicates that it is rapidly hydrolyzed and that both triglyceride and nonesterified forms are excreted in the urine to a very low extent. The tissue uptake rate of NEDA is consistent with the possibility of achieving substantial energy delivery, should it be added to parenteral nutrition formulations. Furthermore, the amount of sodium administered with the triglyceride form is one-half of that necessary with the free diacid.

scholarly journals Comparative Pharmacokinetics, Tissue Distributions, and Effects on Renal Function of Novel Polymeric Formulations of Amphotericin B and Amphotericin B-Deoxycholate in Rats

2000 ◽  
Vol 44 (4) ◽  
pp. 898-904 ◽  
Author(s):  
Iciar Echevarría ◽  
Celia Barturen ◽  
María Jesús Renedo ◽  
Iñaki F. Trocóniz ◽  
M. Carmen Dios-Viéitez
Keyword(s):  
Renal Function ◽  
Amphotericin B ◽  
High Performance ◽  
Drug Exposure ◽  
Compartment Model ◽  
Drug Uptake ◽  
Parameter Estimates ◽  
Tissue Samples ◽  
Plasma Creatinine Level ◽  
Male Wistar Rats

ABSTRACT The pharmacokinetic profiles of a traditional formulation of amphotericin B (Fungizone) and novel nanosphere and mixed micelle delivery systems developed for amphotericin B were compared and described. Six groups of male Wistar rats received intravenous injections of the different formulations. Plasma and tissue samples were obtained at 11 different times after dosing, with three animals used each time. The amphotericin B concentrations in plasma and tissues were analyzed by high-performance liquid chromatography. The plasma drug concentration-time profiles were best described by a two-compartment model. Models that described the observed single or double peak disposition kinetics in kidney, liver, and spleen were also developed. Parameter estimates from those models show that components of the formulation such as poloxamer 188, which is present in all new formulations, seem to play an important role in the rate of drug uptake by the tissues; in general, the levels of amphotericin B in tissues were increased after the administration of the new formulations compared with those after the administration of Fungizone. The increment in the baseline plasma creatinine level was used as an index of renal function. All formulations increased this baseline value, but the novel formulations exhibited fewer renal effects than Fungizone did. However, a direct relationship between drug exposure in the kidneys and development of renal damage could not be found.

scholarly journals Kinetics of dodecanedioic acid and effect of its administration on glucose kinetics in rats

1997 ◽  
Vol 78 (1) ◽  
pp. 143-153 ◽  
Author(s):  
Alessandro Bertuzzi ◽  
Geltrude Mingrone ◽  
Andrea De Gaetano ◽  
Alberto Gandolfi ◽  
Aldo V Greco ◽  
...  
Keyword(s):  
Parenteral Nutrition ◽  
Urinary Excretion ◽  
Compartment Model ◽  
Tissue Uptake ◽  
Glucose Kinetics ◽  
Population Means ◽  
Reversible Binding ◽  
Male Wistar Rats ◽  
Total Body ◽  
Dodecanedioic Acid

Dodecanedioic acid (C12), a saturated aliphatic dicarboxylic acid with twelve C atoms, was given as an intraperitoneal bolus to male Wistar rats, with the aim of evaluating C12 suitability as an energy substrate for parenteral nutrition. The 24 h urinary excretion of C12 was 3·9% of the administered dose. C12 kinetics were investigated by a one-compartment model with saturable tissue uptake and reversible binding to plasma albumin. The analysis of plasma concentration and urinary excretion data from different animals yielded the population means of the kinetic parameters: renal clearance was 0·72ml/min per kg body weight (BW) (much smaller than inulin clearance in the rat), and maximal tissue uptake was 17·8 μmol/min per kg BW corresponding to 123·7 J/min per kg BW. These results encourage the consideration of C12 as a possible substrate for parenteral nutrition. To investigate the effect of C12 administration on glucose kinetics, two other groups of rats, one treated with an intraperitoneal bolus of C12 and the other with saline, were subsequently given an intravenous injection of D-[U-14C]glucose in a tracer amount. Radioactivity data of both control and C12-treated rats were analysed by means of a two-compartment kinetic model which takes into account glucose recycling. The estimates of glucose pool size (2·3 mmol/kg BW) and total-body rate of disappearance (82·1 μmol/min per kg BW) in control rats agreed with published values. In C12-treated rats, the rate of disappearance appeared to be reduced to 36·7 μmol/min per kg BW and the extent of recycling appeared to be negligible.

scholarly journals Disposition Kinetics of Amitraz in Lactating Does

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4769
Author(s):  
Sathish Nanjundappa ◽  
Suresh Narayanan Nair ◽  
Darsana Udayan ◽  
Sreelekha Kanapadinchareveetil ◽  
Mathew Jacob ◽  
...  
Keyword(s):  
High Performance ◽  
Area Under The Curve ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Health Concern ◽  
Laboratory Animals ◽  
Disposition Kinetics ◽  
Kinetics Of ◽  
Apparent Volume Of Distribution ◽  
Dermal Application

Amitraz, a member of the formamidine pesticide family, commonly used for ectoparasite control, is applied as a dip or low-pressure hand spray to cattle and swine, and the neck collar on dogs. Data on amitraz were generated mainly on laboratory animals, hens, dogs, and baboons. The data on the toxicity and disposition of amitraz in animals and its residues in the milk are inadequate. Therefore, the present study was intended to analyze the disposition kinetics of amitraz and its pattern of elimination in the milk of lactating does after a single dermal application at a concentration of 0.25%. Blood at predetermined time intervals and milk twice daily were collected for eight days post application. The drug concentration was assayed by high-performance liquid chromatography (HPLC). Amitraz was detected in whole blood as early as 0.5 h, which attained a peak concentration at 12 ± 5 h, followed by a steady decline; however, detection persisted until 168 h. Amitraz was present in the blood at its 50% Cmax even after 48 h, and was still detectable after 7 days. The disposition after a single dermal application was best described non-compartmentally. The mean terminal half-life (t1/2), mean residence time (MRT), and area under the curve (AUC0–t) were 111 ± 31 h, 168 ± 39 h, and 539 ± 211 µg/mL/h, respectively. The apparent volume of distribution (Vdarea) was 92 ± 36 mL/g with an observed clearance (Cl) of 0.57 ± 0.33 mL/kg/h. Thus, the drug was well absorbed, widely distributed and slowly eliminated from the animal body. Amitraz achieved milk concentration approximating 0.2 per cent of the total dose after a single exposure and the steady-state elimination of amitraz in milk above the recommended maximum residue limit (MRL) of 0.01 mg/kg can act as a source of public health concern when applied on lactating animals.

67Gallium Kinetics in the Blood of Patients with Malignant Tumors

1983 ◽  
Vol 22 (03) ◽  
pp. 155-158
Author(s):  
M. K. Maiga ◽  
P. Koeppe ◽  
F. Keller
Keyword(s):  
Kinetic Parameters ◽  
Malignant Tumors ◽  
Clinical Investigation ◽  
Compartment Model ◽  
Bimodal Distribution ◽  
Volume Of Distribution ◽  
Least Square ◽  
Peripheral Compartment ◽  
Limited Information ◽  
Tumor Patients

67GaIlium was injected into 60 patients with malignant tumors and into 42 patients in whom malignant tumors had been excluded by clinical investigation. 67Ga kinetics in blood were evaluated by non-linear least square regression computer analysis according to an open 2-compartment model where elimination proceeds from the peripheral compartment. Parameters of 67Ga kinetics in tumor patients showed a bimodal distribution, as was also the case in patients without tumors. No difference could be demonstrated between kinetic parameters of tumor patients and patients without tumors. In 4 patients, 67Ga kinetics could be evaluated before and after treatment of their malignant tumors, but a decrease in the volume of distribution was the single alteration of kinetic parameters occurring after treatment. This decrease may be explained by a smaller peripheral compartment resulting from the loss of tumor mass after treatment. Nevertheless, we conclude that the evaluation of 67Ga kinetics in blood will provide only limited information about the presence, size and growth rate of malignant tumors in man.

Pharmacokinetics and metabolism of 4'-iodo-4'-deoxy-doxorubicin in humans.

1992 ◽  
Vol 10 (7) ◽  
pp. 1183-1190 ◽  
Author(s):  
J Robert ◽  
J P Armand ◽  
S Huet ◽  
M Klink-Alakl ◽  
G Recondo ◽  
...  
Keyword(s):  
Blood Cell ◽  
High Performance ◽  
Parent Compound ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Parent Drug ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Hematologic Toxicity ◽  
Cell Counts

PURPOSE 4'-iodo-4'-deoxydoxorubicin is a new anthracycline that currently is under clinical evaluation. To improve the management of future trials, we have determined its pharmacokinetics and metabolism during a phase I/II study and have tried to relate the parameters obtained to the hematologic toxicity of the drug in terms of the survival of blood cells. PATIENTS AND METHODS The pharmacologic study included 19 patients who were entered at dose levels that ranged between 6 and 90 mg/m2; nine patients were treated at 80 mg/m2, which is close to the maximum recommended dose level. Blood sampling was performed from the end of the bolus infusion to 48 hours after treatment. Drug and metabolites were extracted and analyzed by high-performance liquid chromatography (HPLC), and the data were processed by nonlinear fitting to multicompartment models. RESULTS Plasma concentrations were best fitted to a three-compartment model with half-lives of 5.2 minutes, 0.79 hours, and 10.3 hours. The total body clearance and volume of distribution at steady state were high (350 L/h/m2 and 2,065 L/m2). The drug was metabolized extensively to a 13-dihydroderivative, 4'-iodo-4'-deoxy-doxorubicinol; the mean area under the curve (AUC) ratio metabolite/parent drug was the highest observed ever for an anthracycline (12.1 +/- 7.4); the metabolite was cleared from the plasma with an elimination half-life of 15.3 hours. The AUCs of the parent compound and its metabolite were related linearly to the dose administered, and showed no saturation phenomenon. Urinary excretion was studied in nine patients and showed a cumulative elimination of less than 6% of the dose administered, two thirds of which were eliminated in the first 12 hours after injection. Ninety-three percent to 100% of the elimination of fluorescent compounds occurred in the form of the metabolite. Drug concentration in five tumor samples showed a rapid uptake of the drug from plasma and a preferential uptake of the parent drug compared with the metabolite. Blood cell counts after 4'-iodo-4'-deoxydoxorubicin treatment showed significant correlations among the surviving fractions of both granulocytes and platelets and the AUCs of the parent drug and its metabolite; the most significant correlations were obtained for the granulocytes and the metabolite. Significant correlations between AUCs and blood-cell survivals were maintained, even if only the nine patients treated at the dose of 80 mg/m2 were taken into account for the computation. CONCLUSIONS Our results especially show that myelosuppression that is induced by 4'-iodo-4'-deoxydoxorubicin can be well predicted by the measure of the AUC of the drug and its metabolite. This could be used for the further development of the drug toward high-dosage schedules.

Influence or age and sex on the kinetics of intravenously administered L-phenylalanine.

1982 ◽  
Vol 28 (1) ◽  
pp. 204-206 ◽  
Author(s):  
R Jagenburg ◽  
C G Regårdh ◽  
S Rödjer
Keyword(s):  
Total Body Clearance ◽  
Kinetic Studies ◽  
Compartment Model ◽  
Peripheral Compartment ◽  
Two Compartment Model ◽  
Total Body ◽  
Kinetics Of ◽  
Effect Of Age ◽  
Age And Sex ◽  
Body Clearance

Abstract We studied the kinetics of intravenously administered L-phenylalanine with respect to the effect of age and sex, using a two-compartment model. We found that the volume of the peripheral compartment and total body clearance decrease with age. The sex-related influence was less obvious when distribution volumes and total body clearance were corrected for differences in body size. We emphasize the necessity of having age-matched control subjects in kinetic studies.

scholarly journals Pharmacokinetics, urinary excretion and plasma protein binding of ofloxacin in water buffalo calves (Bubalus bubalis)

2013 ◽  
Vol 84 (1) ◽  
Author(s):  
Ajay K. Ola ◽  
Harpal S. Sandhu ◽  
Vinod K. Dumka ◽  
Bibhuti Ranjan
Keyword(s):  
Urinary Excretion ◽  
Half Life ◽  
High Performance ◽  
Water Buffalo ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Buffalo Calves ◽  
Time Curve

Pharmacokinetics and urinary excretion of an intravenous dose of 5 mg.kg–1 ofloxacin were investigated in water buffalo calves. Plasma concentrations of ofloxacin were determined by high-performance liquid chromatography. Ofloxacin was rapidly distributed from the central to the peripheral compartment as evidenced by a short distribution half-life (0.09 h ± 0.003 h) and high K12 (4.7 h–1 ± 0.1 h–1), and was detected in plasma for 8 h. The large volume of distribution (2.48 L.kg–1 ± 0.18 L.kg–1) obtained in this study indicated high distribution of ofloxacin in water buffalo calves. The elimination half-life, the area under the plasma drug concentration–time curve and total body clearance were 2.11 h ± 0.13 h, 6.20 µg.mL—1 ± 0.23 µg.mL—1.h and 0.81 mL.kg–1.h–1 ± 0.03 mL.kg–1.h–1, respectively. About 18.7% of administered drug was bound to plasma proteins and approximately 32.5% of the administered dose was recovered in urine within 48 h. The results of the study indicated a favourable pharmacokinetic profile of ofloxacin in water buffalo calves, which suggests that ofloxacin may be effective against urinary pathogens in this species.

Influence of Hypovolemia on the Pharmacokinetics and Electroencephalographic Effect of γ-Hydroxybutyrate in the Rat

2002 ◽  
Vol 97 (5) ◽  
pp. 1218-1226 ◽  
Author(s):  
Diederik K. Van Sassenbroeck ◽  
Peter De Paepe ◽  
Frans M. Belpaire ◽  
Paul A. Boon ◽  
Walter A. Buylaert
Keyword(s):  
Blood Pressure ◽  
High Performance ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Control Procedure ◽  
Time Data ◽  
Time Curve ◽  
Concentration Time ◽  
Gamma Hydroxybutyrate ◽  
Significant Difference

Background Hypovolemia alters the effect of propofol in the rat by influencing the pharmacokinetics and the end organ sensitivity. We now studied the effect of hypovolemia on the anesthetic gamma-hydroxybutyrate (GHB) because in contrast with propofol it increases blood pressure. Methods Thirty-two rats were randomly assigned to undergo moderate hypovolemia or a control procedure. Each rat received either an infusion of sodium-GHB (390 mg x kg(-1) x 5 min(-1)) or the same volume of an equimolar solution of sodium chloride (6.9%). Plasma samples were taken for GHB assay (high-performance liquid chromatography) and the electroencephalography and blood pressure values were recorded. A two-compartment model with Michaelis-Menten elimination was fitted to the concentration-time data and a sigmoid E(max) model to the electroencephalographic effect effect site concentration curve allowing the study of the end organ sensitivity. Results Plasma concentration-time curves and the total volume of distribution in hypovolemic and normovolemic rats were comparable with only small but significant differences in central volume of distribution and the intercompartmental clearance. There was no significant difference either in the distribution from the plasma to the brain (k(e0)) or in the end organ sensitivity (EC50 = 335 +/- 76 microg/ml in control vs. 341 +/- 89 microg/ml in hypovolemic rats). GHB temporarily increased mean arterial pressure in both groups, which cannot be explained by the sodium salt alone. Conclusions Hypovolemia does not influence the overall concentration-time curve of GHB and induces no changes in the electroencephalographic effect of GHB in the rat. This difference with propofol may be due to the fact that it increases blood pressure but also due to its different pharmacokinetic properties.

scholarly journals Pregnancy-Related Effects on Tenofovir Pharmacokinetics: a Population Study with 186 Women

2011 ◽  
Vol 56 (2) ◽  
pp. 857-862 ◽  
Author(s):  
Sihem Benaboud ◽  
Déborah Hirt ◽  
Odile Launay ◽  
Emmanuelle Pannier ◽  
Ghislaine Firtion ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Parameter Estimates ◽  
Population Parameter ◽  
Linear Absorption ◽  
Two Compartment Model ◽  
Apparent Clearance ◽  
Elimination Clearance

ABSTRACTAccording to the European AIDS Clinical Society, tenofovir disoproxil fumarate can be used in HIV-infected pregnant women if started prior to pregnancy, although no data are available on the pharmacokinetics of tenofovir (TFV) during pregnancy. The aim of this study was to describe TFV pharmacokinetics in HIV-infected women and to evaluate the effect of pregnancy on TFV disposition. Samples were collected according to a therapeutic drug monitoring in 186 women, including 46 pregnant women treated with TFV and retrospectively analyzed by a population approach. TFV pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. The mean population parameter estimates (between-subject variability) were as follows: absorption rate constant, 0.56 h−1; elimination clearance, 59.9 liters h−1(0.436); central volume of distribution, 552 liters (1.96); intercompartmental clearance, 172 liters/h; and peripheral volume of distribution, 1,390 liters. Pregnant women had a 39% higher apparent clearance compared to nonpregnant women. Apparent clearance significantly decreased with age. In order to obtain an exposure similar to the known exposure in adults and guarantee similar trough concentrations (Cmin) as observed in adults, an increase in the TFV dose should be considered for women from the second trimester to delivery.

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