Letters to the Editor

We appreciate the comments of Weinberger et al and Spino et al. The equation utilized in our original report to calculate the apparent volume of distribution (V) was in error, as it was based on determinations for drugs that exhibit monoexponential elimination following a single intravenous dose. The correct formula for oral dosing at steady state with a drug obeying one-compartment model kinetics is: V = F.X0/AUCτ. K, where F is the total fraction of dose reaching systemic circulation, X0, is the dose, AUCτ is the area under the curve during a dosing interval; K is the elimination rate constant.1

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Letters to the Editor

PEDIATRICS ◽

10.1542/peds.68.4.601 ◽

1981 ◽

Vol 68 (4) ◽

pp. 601-602

Author(s):

M. Spino ◽

J. J. Thiessen ◽

A. Isles ◽

H. Levison ◽

S. M. MacLeod

Keyword(s):

Clinical Application ◽

Drug Concentration ◽

Apparent Volume ◽

Volume Of Distribution ◽

Intravenous Dose ◽

Single Intravenous Dose ◽

Letters To The Editor ◽

Potential Clinical Application ◽

Apparent Volume Of Distribution

We found the report by Feldman et al1 interesting with potential clinical application. However, we would like to point out an error in their determination of the apparent volume of distribution (V) and comment on both their methodology and results. They state that V was calculated by dividing the dose of the drug by the extrapolated y intercept for drug concentration at time 0. This method is correct for a drug which exhibits monoexponential elimination following a single intravenous dose.

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Disposition Kinetics of Amitraz in Lactating Does

Molecules ◽

10.3390/molecules26164769 ◽

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.

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Altered Aminoglycoside Pharmacokinetics in the Critically Ill

Anaesthesia and Intensive Care ◽

10.1177/0310057x8801600406 ◽

1988 ◽

Vol 16 (4) ◽

pp. 418-422 ◽

Cited By ~ 41

Author(s):

M. J. Beckhouse ◽

I. M. Whyte ◽

P. L. Byth ◽

J. C. Napier ◽

A. J. Smith

Keyword(s):

Critically Ill ◽

Compartment Model ◽

Serum Levels ◽

Apparent Volume ◽

Volume Of Distribution ◽

Pharmacokinetic Data ◽

Post Dose ◽

Apparent Volume Of Distribution ◽

Trough Levels ◽

Volumes Of Distribution

We studied prospectively 49 patients being treated in an intensive care unit with aminoglycosides for gram-negative sepsis. Pharmacokinetic data were calculated from three post-dose serum levels using a one-compartment model. Doses required to achieve peak levels between 5 and 10 mg/l with trough levels approximately 1.0 mg/l ranged between 2 and 12 mg/kg per day (mean dose 7 mg/kg per day). During therapy 60% of the patients had a change in their apparent volume of distribution (Vd) of greater than 20%. These patients were likely to have confirmed infection and to be febrile at the start of treatment. Two to three weeks after discharge ten patients were restudied after a single dose of aminoglycoside. There was a reduction in mean Vd from 0.24 to 0.18 l/kg (P < 0.02). Critically ill patients have significantly larger volumes of distribution and may require larger doses per kilogram of body weight of aminoglycoside to achieve therapeutic concentrations. Due to considerable variation in kinetic parameters, the use of standard doses or dosing nomograms is not recommeded.

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An HPLC–MS/MS method for quantitation of trelagliptin and application in a comparative pharmacokinetic study

Bioanalysis ◽

10.4155/bio-2018-0238 ◽

2019 ◽

Vol 11 (19) ◽

pp. 1755-1765

Author(s):

Ying Han ◽

Liqing Chen ◽

Wei Liu ◽

Xin Xin ◽

Lingwei Meng ◽

...

Keyword(s):

Ion Pairs ◽

Area Under The Curve ◽

Internal Standard ◽

Apparent Volume ◽

Volume Of Distribution ◽

Distribution Area ◽

Comparative Pharmacokinetic ◽

Positive Mode ◽

First Time ◽

Apparent Volume Of Distribution

Aim: A sensitive HPLC–MS/MS approach was established to quantify trelagliptin and explore the pharmacokinetic characteristics in rats for up to 7 days. Meanwhile, the pharmacokinetic differences of trelagliptin were investigated for the first time. Results/methodology: The ion pairs of m/z 358.2→341.2 for trelagliptin and m/z 340.3→116.1 for alogliptin (internal standard) were detected in positive mode. Trelagliptin displayed a good linearity in the range of 4–4000 ng/ml (r2 = 0.9997) with a mean recovery rate of 86.9–94.1%. Discussion/conclusion: Compared with normal groups, the T1/2, apparent volume of distribution, area under the curve and bioavailability in model rats were significantly increased while the apparent plasma clearance decreased. The approach is proved to be straightforward and appropriate for quantitation of trelagliptin and application in pharmacokinetics studies.

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Comparative Toxicokinetics of MMB4 DMS in Rats, Rabbits, Dogs, and Monkeys Following Single and Repeated Intramuscular Administration

International Journal of Toxicology ◽

10.1177/1091581813488631 ◽

2013 ◽

Vol 32 (4_suppl) ◽

pp. 38S-48S ◽

Cited By ~ 1

Author(s):

S. Peter Hong ◽

Seth T. Gibbs ◽

Dean J. Kobs ◽

Michael A. Hawk ◽

Claire R. Croutch ◽

...

Keyword(s):

Area Under The Curve ◽

Apparent Volume ◽

Systemic Circulation ◽

Volume Of Distribution ◽

Drug Dose ◽

Absolute Bioavailability ◽

Sprague Dawley ◽

Preclinical Species ◽

Repeated Administrations ◽

Time Courses

1,1′-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Time courses of MMB4 concentrations in plasma were characterized following 7-day repeated intramuscular (IM) administrations of MMB4 DMS to male and female Sprague-Dawley rats, New Zealand White rabbits, beagle dogs (single dose only), and rhesus monkeys at drug dose levels used in earlier toxicology studies. In general, there were no significant differences in MMB4 toxicokinetic (TK) parameters between males and females for all the species tested in these studies. After a single IM administration to rats, rabbits, dogs, and monkeys, MMB4 DMS was rapidly absorbed, resulting in average Tmax values ranging from 5 to 30 minutes. Although Cmax values did not increase dose proportionally, the overall exposure to MMB4 in these preclinical species, as indicated by area under the curve (AUC) extrapolated to the infinity (AUC∞) values, increased in an approximately dose-proportional manner. The MMB4 DMS was extensively absorbed into the systemic circulation after IM administration as demonstrated by greater than 80% absolute bioavailability values for rats, rabbits, and dogs. Repeated administrations of MMB4 DMS for 7 days did not overtly alter TK parameters for MMB4 in rats, rabbits, and monkeys (150 and 300 mg/kg/d dose groups only). However, Cmax and AUC values decreased in monkeys given 450 and 600 mg/kg IM doses of MMB4 DMS following repeated administrations for 7 days. Based on the TK results obtained from the current study and published investigations, it was found that the apparent volume of distribution and clearance values were similar among various preclinical species, except for the rat.

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The Pharmacokinetics of Buserelin after Intramuscular Administration in Pigs and Cows

10.21203/rs.3.rs-900328/v1 ◽

2021 ◽

Author(s):

Zhengrong Gao ◽

Yu Liu ◽

Yuxin Yang ◽

Yuying Cao ◽

Jicheng Qiu ◽

...

Keyword(s):

Area Under The Curve ◽

Apparent Volume ◽

Ultra Performance Liquid Chromatography ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Elimination Half ◽

Liquid Chromatography Tandem Mass ◽

Stability Method ◽

Apparent Volume Of Distribution

Abstract Background: Buserelin is a LHRH agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not clearly understood. This study was designed to develop a sensitive method to determine the concentration of buserelin and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows. Results: A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studies in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC0-t) was 25.02 ± 6.93 h·ng/mL for pigs and 5.63 ±1.86 h·ng/mL for cows. The maximum plasma concentration (Cmax) and time to reach the maximum concentration (tmax) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ±0.27 h for cows, respectively. The apparent volume of distribution (Vz) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t1/2λz), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals. Conclusion: This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.

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Estimation of Pharmacokinetic Parameters at Steady-State in Patients

Drug Intelligence & Clinical Pharmacy ◽

10.1177/106002807801201005 ◽

1978 ◽

Vol 12 (10) ◽

pp. 612-616 ◽

Cited By ~ 1

Author(s):

James W. Crow ◽

Milo Gibaldi

Keyword(s):

Steady State ◽

Rate Constant ◽

Elimination Rate ◽

Simulated Data ◽

Apparent Volume ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Total Clearance ◽

Dosing Intervals ◽

Apparent Volume Of Distribution

A method to characterize the pharmacokinetics of a drug in a patient receiving it chronically is proposed. In principle, such characterization may be carried out by obtaining one or more drug concentration in plasma-time values from several different dosing intervals, combining the data to create a composite dosing interval representative of the steady-state situation and fitting the data to an appropriate equation. The method was evaluated using simulated data based on the average pharmacokinetic parameters of theophylline in children. Reasonable estimates of the elimination rate constant and apparent volume of distribution may be obtained, but the estimation of the absorption rate constant presents formidable problems. The method appears to be most useful for obtaining very accurate estimates of total clearance.

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Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00943-05 ◽

2006 ◽

Vol 50 (11) ◽

pp. 3548-3555 ◽

Cited By ~ 36

Author(s):

Vincent Jullien ◽

Saïk Urien ◽

Déborah Hirt ◽

Constance Delaugerre ◽

Elisabeth Rey ◽

...

Keyword(s):

Population Analysis ◽

Combined Treatment ◽

Elimination Rate ◽

Compartment Model ◽

Apparent Volume ◽

Volume Of Distribution ◽

Mixed Effect ◽

Nonlinear Mixed Effect ◽

Nonlinear Mixed Effect Modeling ◽

Age And Sex

ABSTRACT The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.

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A Population Pharmacokinetic Approach to Describe Cephalexin Disposition in Adult and Aged Dogs

Veterinary Medicine International ◽

10.1155/2014/789353 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Ana Paula Prados ◽

Paula Schaiquevich ◽

Verónica Kreil ◽

Agustina Monfrinotti ◽

Pamela Quaine ◽

...

Keyword(s):

Plasma Concentrations ◽

Elimination Rate ◽

Compartment Model ◽

Apparent Volume ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Studies ◽

Mixed Breed ◽

Pharmacokinetic Approach

This study was conducted in order to characterize the pharmacokinetics of orally administered cephalexin to healthy adult and aged dogs, using a population pharmacokinetic approach. Two hundred and eighty-six cephalexin plasma concentrations obtained from previous pharmacokinetic studies were used. Sex, age, pharmaceutical formulation, and breed were evaluated as covariates. A one-compartment model with an absorption lag-time (Tlag) best described the data. The final model included age (adult; aged) on apparent volume of distribution (Vd/F), apparent elimination rate (ke/F), and Tlag; sex (female; male) on ke/F, and breed (Beagle; mixed-breed) on Vd/F. Addition of the covariates to the model explained 78% of the interindividal variability (IIV) in Vd/F, 36% in ke/F, and 24% in Tlag, respectively. Formulation did not affect the variability of any of the pharmacokinetic parameters. Tlag was longer, whereas Vd/F and ke/F were lower in aged compared to adult animals; in female aged dogs ke/F was lower than in male aged dogs; however, the differences were of low magnitude. Different disposition of cephalexin may be expected in aged dogs.

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Influence of Resveratrol on the Pharmacokinetics and Pharmacodynamics of Naproxen: Involvement of CYP1A2 Inhibition

Pharmaceutics and Pharmacology Research ◽

10.31579/2693-7247/004 ◽

2018 ◽

Vol 1 (1) ◽

pp. 01-03

Author(s):

Prasad Neerati

Keyword(s):

Single Dose ◽

Area Under The Curve ◽

Treatment Phase ◽

Apparent Volume ◽

Volume Of Distribution ◽

Maximum Plasma ◽

Time Intervals ◽

Novel Approach ◽

Gastrointestinal Side Effects ◽

Apparent Volume Of Distribution

The purpose of the present study was to assess the effect of resveratrol (RSV) on the pharmacokinetics of naproxen (NAP) in rats. A single dose of RSV 30mg/kg was administered once during treatment phase. A single dose of NAP 25mg/kg was administered after RSV treatment. The blood samples were collected after NAP dosing at predetermined time intervals and analyzed by HPLC. In comparison with the control, RSV pretreatment significantly enhanced maximum plasma concentration (Cmax), area under the curve (AUC), and half life (t1/2) and significantly decreased apparent oral clearance (CL/F) and apparent volume of distribution (Vd/F), while there was no significant change observed in time to reach maximum concentration (tmax) of NAP. The results suggest that the altered pharmacokinetics of NAP might be attributed to RSV-mediated inhibition of CYP1A2 enzyme. Therefore, combination therapy of NAP along with RSV may represent a novel approach to reduce dosage and results in reduced gastrointestinal side effects of NAP.

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