scholarly journals The intravenous pharmacokinetics of diminazene in healthy dogs

2009 ◽  
Vol 80 (4) ◽  
Author(s):  
V. Naidoo ◽  
M.S.G. Mulders ◽  
G.E. Swan
Keyword(s):  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Secondary Peak ◽  
German Shepherd ◽  
Plasma Pharmacokinetics ◽  
Healthy Dogs ◽  
Over 40 Years

Diminazene remains one of South Africa's most commonly used antiprotozoal agents for the management of babesiosis in dogs . Although the drug has been on the market for over 40 years, its intravenous pharmacokinetics are poorly known. To better understand the pharmacokinetics of the drug Berenil®, it was reconstituted in sterile water and administered intravenously to 6 adult German shepherd dogs. All 6 dogs demonstrated the previously described secondary peak in the plasma concentration versus time profile. The plasma pharmacokinetics for diminazene are described by both non-compartmental and compartmental models. From non-compartmental analysis, the area under curve to the last sample point (AUClast), clearance (CL) and volume of distribution (Vz) were 4.65±1.95 ng/mℓ/h, 0.77±0.18 ℓ/kg/h and 2.28±0.60 ℓ/kg, respectively. For compartmental modelling, the plasma concentrations were fitted to both a 2-compartmental open model and a recirculatory enterohepatic model. From the recirculation model, the rate of release and re-entry into the central compartment varied markedly with the rate of release from the gall bladder (Ttom) being estimated at 27 ± 20.90 h. Once released, drug re-entry into the central compartment was variable at 9.70±5.48 h. With normal biliary excretion time being about 2 h, this indicates that the redistribution cannot be occurring physiologically from the bile. Although it was not possible to identify the site from which sequestration and delayed release is occurring, it is believed that it is most likely from the liver. The study therefore showed that the secondary peak described for the pharmacokinetics of intramuscular administered diminazene in the dog is not related to biphasic absorption.

scholarly journals Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks

2007 ◽  
Vol 51 (5) ◽  
pp. 1822-1826 ◽  
Author(s):  
Olanrewaju Okusanya ◽  
Alan Forrest ◽  
Robin DiFrancesco ◽  
Sanela Bilic ◽  
Susan Rosenkranz ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Information Criteria ◽  
Secondary Peak ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Healthy Human ◽  
Two Compartment Model

ABSTRACT Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.

scholarly journals Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1278-1285 ◽  
Author(s):  
Elizabeth A. Maxwell ◽  
Tamara I. King ◽  
Shyam H. Kamble ◽  
Kanumuri Siva Rama Raju ◽  
Erin C. Berthold ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Ultra Performance Liquid Chromatography ◽  
Volume Of Distribution ◽  
Pharmacokinetic Studies ◽  
Beagle Dogs ◽  
Limit Of Quantification ◽  
Significant Information ◽  
Pharmacokinetic Properties

AbstractMitragynine is the most abundant psychoactive alkaloid derived from the leaves of Mitragyna speciosa (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (Vd, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (Cmax, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a Cmax of 31.5 ± 3.3 ng/mL and a Tmax of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.

Pharmacokinetic/Pharmacodynamic Analysis of Meropenem for the Treatment of Nosocomial Pneumonia in Intracerebral Hemorrhage Patients by Monte Carlo Simulation

2017 ◽  
Vol 51 (11) ◽  
pp. 970-975 ◽  
Author(s):  
Lingti Kong ◽  
Yan Tang ◽  
Xiaohua Zhang ◽  
Guoyu Lu ◽  
Meiling Yu ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Intracerebral Hemorrhage ◽  
Nosocomial Pneumonia ◽  
High Performance ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Dosing Regimens ◽  
Total Body

Background: Nosocomial pneumonia (NP) is a frequent complication among patients with intracerebral hemorrhage (ICH). However, there are currently no pharmacokinetic (PK) and pharmacodynamic (PD) data to guide meropenem dosing in these patients. Objective: To investigate the PK/PD properties of meropenem in these patients and whether the usual dosing regimens of meropenem (2-hour infusion, 1 g, every 8 hours) was suitable. Methods: A total of 11 patients with a diagnosis of ICH complicated with NP were selected in the emergency internal medicine and treated with a 1-g/2-hours extended infusion model. The plasma concentrations of meropenem were determined by high-performance liquid chromatography. PK parameters were estimated by plasma concentration versus time profile using WinNonlin software. The probability of target attainments (PTAs) of meropenem at different minimum inhibitory concentrations (MICs) based on percentage time that concentrations were above the minimum inhibitory concentration (%T>MIC) value were performed by Monte Carlo simulation. Results: The volume of distribution and total body clearance of meropenem were 55.55 L/kg and 22.89 L/h, respectively. Using 40%T>MIC, PTA was >90% at MICs ≤4 µg/mL. Using 80% or 100%T>MIC, PTA was >90% only at MICs ≤1 µg/mL. Conclusions: The PK/PD profile of dosing regimens tested will assist in selecting the appropriate meropenem regimens for these patients. At a target of 40%T>MIC, the usual dosing regimens can provide good coverage for pathogens with MICs of ≤4 µg/mL. However, when a higher target (80% or 100%) is desired for difficult-to-treat infections, larger doses, prolonged infusions, shorter intervals, and/or combination therapy may be required.

scholarly journals Pharmacokinetic Profile of Kaurenoic Acid after Oral Administration of Araliae Continentalis Radix Extract Powder to Humans

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 253
Author(s):  
Eun-Jeong Choi ◽  
Go-Wun Choi ◽  
Seung-Jeong Yang ◽  
Yong-Bok Lee ◽  
Hea-Young Cho
Keyword(s):  
Plasma Concentrations ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Efflux Transporters ◽  
Peripheral Compartment ◽  
Simple Liquid ◽  
Usual Dose ◽  
Kaurenoic Acid

The objective of this study was to characterize pharmacokinetics (PKs) of kaurenoic acid (KAU) after administration of the clinical usual dose of Araliae Continentalis Radix extract powder to Korean subjects for the first time and evaluate the mechanism of its absorption in vitro. A simple, sensitive, and selective analytical method was developed for the detection of KAU in human plasma. Concentrations of KAU were quantified by ultra-performance liquid chromatography tandem mass spectrometry after simple liquid–liquid extraction. This pharmacokinetic model of KAU was best described by a two-compartment model with first-order absorption. To identify efflux transporters involved in the absorption of KAU, a Caco-2 monolayer model was used. Estimated PK parameters were: systemic clearance, 23.89 L/h; inter-compartmental clearance, 15.55 L/h; rate constant for absorption, 1.72 h−1; volume of distribution of the central compartment, 24.44 L; and volume of distribution of the peripheral compartment, 64.05 L. Results from Caco-2 bidirectional transport study suggested that KAU was a potential substrate of efflux transporters. In summary, PKs of KAU were successfully characterized after administration of a usual dose of Araliae continentalis Radix extract powder in human with the newly developed bioanalytical method and the mechanism of absorption of KAU was identified clearly.

scholarly journals Pharmacokinetics of Luteolin and Metabolites in Rats

2008 ◽  
Vol 3 (12) ◽  
pp. 1934578X0800301 ◽  
Author(s):  
Sasiporn Sarawek ◽  
Hartmut Derendorf ◽  
Veronika Butterweck
Keyword(s):  
Oral Administration ◽  
Intravenous Administration ◽  
Plasma Concentrations ◽  
Maximum Level ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Oral Solution ◽  
Pharmacokinetic Parameters ◽  
Elimination Phase ◽  
Intravenous And Oral Administration

The pharmacokinetic parameters of luteolin and its glucuronide/sulfate conjugates were studied in rats after a single 50 mg/kg dose of luteolin administered as intravenous bolus or oral solution. Plasma and urine samples were enzymatically hydrolyzed to determine conjugate concentrations of luteolin. Noncompartmental analysis revealed a half-life of 8.94 h for free (unconjugated) and 4.98 h for conjugated luteolin following intravenous administration. Following oral administration, plasma concentrations of luteolin attained a maximum level of 5.5 μg/mL at 5 min and decreased to below LOQ (100 ng/mL) after 1 h. Ke could not be calculated because the elimination phase was below LOQ. The low bioavailability (F) of luteolin, 4.10% at a dose of 50 mg/kg, is presumably due to the significant first pass effect. For i.v. administration, the maximum concentration of luteolin was 23.4 μg/mL at 0 h. The plasma concentration versus time profile of luteolin was biphasic, subdivided into a distribution phase and a slow elimination phase for oral and intravenous administration. Luteolin was found to have a large volume of distribution and a high clearance. Double peaks were found after intravenous and oral administration, suggesting enterohepatic recirculation.

scholarly journals Plasma levels of a methadone constant rate infusion and their corresponding effects on thermal and mechanical nociceptive thresholds in dogs

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
T. Amon ◽  
S. B. R. Kästner ◽  
M. Kietzmann ◽  
J. Tünsmeyer
Keyword(s):  
Plasma Concentrations ◽  
Isotonic Saline ◽  
Volume Of Distribution ◽  
Pharmacokinetic Data ◽  
Thermal Thresholds ◽  
Treatment Groups ◽  
Mechanical Threshold ◽  
Constant Rate ◽  
Healthy Dogs ◽  
Rate Infusion

Abstract Background The present study aimed to collect pharmacokinetic data of a methadone continuous rate infusion (CRI) and to investigate its effect on mechanical and thermal nociceptive thresholds. Seven, 47 to 54 months old beagle dogs, weighing 9.8 to 21.2 kg, were used in this experimental, randomized, blinded, placebo-controlled crossover study. Each dog was treated twice with either a methadone bolus of 0.2 mg kg− 1 followed by a 0.1 mg kg− 1 h− 1 methadone CRI (group M) or an equivalent volume of isotonic saline solution (group P) for 72 h. Mechanical and thermal thresholds, as well as vital parameters and sedation were measured during CRI and for further 24 h. Blood samples for methadone plasma concentrations were collected during this 96 h period. Results Percentage thermal excursion (%TE) increased significantly from baseline (BL) until 3 h after discontinuation of CRI in M. Within P and between treatment groups differences were not significant. Mechanical threshold (MT) increased in M until 2 h after CRI discontinuation. Bradycardia and hypothermia occurred in M during drug administration and dogs were mildly sedated for the first 47 h. Decreased food intake and regurgitation were observed in M in five and four dogs, respectively. For methadone a volume of distribution of 10.26 l kg− 1 and a terminal half-life of 2.4 h were detected and a clearance of 51.44 ml kg− 1 min− 1 was calculated. Effective methadone plasma concentrations for thermal and mechanical antinociception were above 17 ng ml− 1. Conclusion A methadone CRI of 0.1 mg kg− 1 h− 1 for 3 days after a loading dose results in steady anti-nociceptive effects in an acute pain model in healthy dogs. Main side effects were related to gastrointestinal tract, hypothermia, bradycardia and sedation.

scholarly journals Pharmacokinetics of l-Arginine in Adults with Moderately Severe Malaria

2008 ◽  
Vol 52 (12) ◽  
pp. 4381-4387 ◽  
Author(s):  
Tsin W. Yeo ◽  
Indri Rooslamiati ◽  
Retno Gitawati ◽  
Emiliana Tjitra ◽  
Daniel A. Lampah ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Time Course ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Time Profile ◽  
No Production ◽  
Natural Time ◽  
Order Polynomial ◽  
No Bioavailability ◽  
Significant Covariates

ABSTRACT Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of l-arginine, the substrate for NO synthase. Supplementation with l-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for l-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g, l-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received l-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] = 52%) and a volume of distribution of 24 liters (CV = 19%). The natural time course of l-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous l-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the Km of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.

Plasma concentration and uterine and ovarian expressions of insulin-like growth factor-2 in dogs with cystic endometrial hyperplasia–pyometra

2021 ◽  
Author(s):  
Nilgün Gültiken ◽  
Murat Yarim ◽  
Gül Fatma Yarim ◽  
Mahmut Sözmen ◽  
Elvan Anadol ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Growth Factor ◽  
Endometrial Hyperplasia ◽  
Endocrine Cells ◽  
Inflammatory Process ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Healthy Dogs ◽  
Group 2 ◽  
Group 1

AbstractThe objective of this study was to investigate the plasma concentrations of insulin-like growth factor-2 (IGF-2) as well as its expression in the uterus and ovary of healthy dogs and those with cystic endometrial hyperplasia (CEH)–pyometra complex. Group 1 (n = 10) included bitches with open cervix pyometra, while Group 2 (n = 7) consisted of clinically healthy bitches in dioestrus. The number of IGF-2 immunopositive interstitial cells was significantly higher in Group 1, whereas in Group 2 there were only two cases in which a few cells were IGF-2 immunopositive. IGF-2 immunopositivity was observed in the endometrial glandular epithelium in both groups. Additionally, interstitial fibroblasts and macrophages in the endometrium were also positive in Group 1. The concentration of plasma IGF-2 was higher in Group 1 than in Group 2 (P < 0.05). The concentration was positively correlated with IGF-2 expression in the endometrial glands (r = 0.926; P < 0.001) in Group 1. However, a negative correlation was present between plasma IGF-2 concentration and IGF-2 expression in the interstitial endocrine cells of the ovary in Group 1 (r = −0.652; P < 0.05). The results suggest that IGF-2 plays an important role during the inflammatory process occurring in bitches with CEH–pyometra complex as well as in the endometrium of healthy bitches in dioestrus.

Assessment of extracellular glucose distribution and glucose transport activity in conscious rats

1995 ◽  
Vol 268 (4) ◽  
pp. E712-E721 ◽  
Author(s):  
J. H. Youn ◽  
J. K. Kim ◽  
G. M. Steil
Keyword(s):  
Glucose Transport ◽  
Insulin Infusion ◽  
Compartmental Analysis ◽  
Time Profile ◽  
Cellular Transport ◽  
Transport Activity ◽  
Conscious Rats ◽  
Distribution Kinetics ◽  
Extracellular Glucose

The effects of insulin on extracellular glucose distribution and cellular glucose transport activity were studied by simultaneously analyzing the plasma kinetics of L-[1-14C]glucose and 3-O-[3H]methylglucose after an intravenous injection during saline or insulin infusion (euglycemic glucose clamp) in conscious rats (n = 7 for each). The time profiles of plasma L-glucose were almost superimposable in the two protocols, and compartmental analysis showed that neither distribution volumes nor distribution rate constants were affected with insulin (P > 0.05 for all), suggesting that glucose distribution within the extracellular space was not influenced with insulin. In contrast, the time profile of plasma 3-O-methylglucose (3-MG) was markedly altered with insulin; the initial decrease was much faster during insulin infusion than during saline infusion, indicating stimulation of 3-MG transport into intracellular spaces with insulin. The 3-MG data were analyzed using a comprehensive model separately describing extracellular distribution and cellular transport of 3-MG by incorporating information on extracellular distribution kinetics obtained from L-glucose data. The combined L-glucose and 3-MG kinetic analysis precisely estimated insulin's effect in vivo to stimulate glucose transport into and out of intracellular spaces. We conclude that 1) insulin does not affect extracellular glucose distribution kinetics or volumes in conscious rats and 2) insulin's effects on cellular glucose transport in vivo can be assessed by simultaneous analysis of plasma L-glucose and 3-MG kinetics.

Clinical Pharmacology and Efficacy of Ticarcillin in Infants and Children

PEDIATRICS ◽  
1978 ◽  
Vol 61 (6) ◽  
pp. 858-863 ◽  
Author(s):  
John D. Nelson ◽  
Helen Kusmiesz ◽  
Sharon Shelton ◽  
Edythe Woodman
Keyword(s):  
Pediatric Patients ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Older Children ◽  
Efficacy Data ◽  
Suspected Sepsis ◽  
Suitable Alternative ◽  
Young Infants ◽  
Limited Efficacy ◽  
Pseudomonas Infection

Ticarcillin was evaluated in 82 neonates and young infants with suspected sepsis and in 16 older children with chronic Pseudomonas infection of the mastoids. The infants also received kanamycin. Individual ticarcillin doses of 75 or 100 mg/kg were given every four, six, or eight hours by intramuscular injection or by a 30-minute intravenous infusion. Mean plasma concentrations one hour after a dose were from 125 to 189 µg/ml, depending on dosage, age, and maturity. Mean plasma half-lives were approximately 5 hours in the first week of life, 2 hours in infants from 1 to 8 weeks, and 0.9 hours in older children. Volume of distribution was approximately twice as great in infants as in children, and plasma clearance rates correlated inversely with age. Limited efficacy data suggest that ticarcillin is a suitable alternative to ampicillin or carbenicillin, when given concurrently with an aminoglycoside, for newborn infections. When given for several days before mastoidectomy and tympanoplasty, ticarcillin sterilized the mastoids in the majority of patients. A new dosage schedule for ticarcillin in pediatric patients is proposed.

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