Oral and Dermal Pharmacokinetics of Triclopyr in Human Volunteers

1989 ◽  
Vol 8 (6) ◽  
pp. 431-437 ◽  
Author(s):  
N.G. Carmichael ◽  
R.J. Nolan ◽  
J.M. Perkins ◽  
R. Davies ◽  
S.J. Warrington
Keyword(s):  
Body Weight ◽  
Oral Administration ◽  
Time Course ◽  
Compartment Model ◽  
Dermal Absorption ◽  
Blood Levels ◽  
Human Volunteers ◽  
Applied Dose ◽  
Dermal Pharmacokinetics ◽  
Oral Doses

Blood levels and urinary excretion of triclopyr, the active ingredient in Garlon® herbicides, were followed in six volunteers given single oral doses of 0.1 and 0.5 mg/kg body weight. Five of these volunteers later received dermal applications of Garlon 4 herbicide formulation equivlant to 3.7 mg triclopyr/kg body weight applied to the forearm. Following oral administration blood levels peaked at 2-3 h and declined to undetectable levels within 48 h; more than 80% of. the dose was found as unchanged triclopyr in the urine. A two-compartment pharmacokinetic model was used to describe the time-course of triclopyr clearance; half-lives for the rapid initial and slower terminal phases were 1.3 h and 5.1 h respectively, and were independent of dose. Due to the slow half-life for dermal absorption (t½ = 16.8 h) the rapid initial elimination phase was obscured and the pharmacokinetics could be simplified by a one-compartment model. An average of 1.37% of the applied dose was recovered in the urine; when corrected for recovery after oral administration this was equivalent to an absorption of 1.65%. Triclopyr is slowly absorbed through skin and is rapidly eliminated. It has very low potential to accumulate in man or to be absorbed through the skin in acutely toxic amounts.

Phosphorus Fluxes in Limnetic Cladocerans: Coupling of Allometry and Compartmental Analysis

1994 ◽  
Vol 51 (5) ◽  
pp. 1055-1064 ◽  
Author(s):  
Yuan Hua Wen ◽  
Alain Vézina ◽  
Robert Henry Peters
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Body Size ◽  
Time Course ◽  
Compartmental Analysis ◽  
Compartment Model ◽  
Size Dependent ◽  
Two Compartment Model ◽  
Metabolic Activities ◽  
Total P

A size-dependent two-compartment model was developed for estimation of 32P turnover and fluxes by limnetic cladocerans in steady state. After feeding on radioactively labelled food, uniformly labelled animals were fed unlabelled cells and the time course of release of tracer followed. Rates of turnover and size-specific fluxes were subsequently fitted to a two-compartment model. The model predicted that steady-state turnover and size-specific fluxes for 32P excretion declined with body weight and that the exponent of weight did not significantly differ from −0.25, suggesting the relationships between total P turnover or flux rates and body size in cladocerans follow the same allometry observed for other organisms and other metabolic activities. However, rate constants for intercompartmental exchanges declined faster than weight−0.25, indicating that their turnover and flux declined much faster with increasing body size than would be expected from general allometry. Size-specific ingestion and assimilation rates of 32P by cladocerans decreased with increasing body size with a slope of the allometric function similar to −0.25.

Obesity Alters the Pharmacokinetics of Vincristine in Mice.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1636-1636
Author(s):  
James W Behan ◽  
Vassilios I Avramis ◽  
Jason P Yun ◽  
Anna Butturini ◽  
Steven D Mittelman
Keyword(s):  
Body Weight ◽  
Specific Activity ◽  
Scintillation Counter ◽  
Compartment Model ◽  
Blood Levels ◽  
Obese Patients ◽  
Obese Mice ◽  
Time Points ◽  
Poor Outcome ◽  
Increased Risk

Abstract Obesity has been associated with increased risk of development and poor outcome from a variety of hematological malignancies. There is a lack of consensus as to how to dose chemotherapies in obese patients, and therefore inadequate dosing represents a potential factor contributing to poor outcome. We have previously shown that diet-induced obese mice transplanted with p190BCR/ABL ALL cells and then treated with vincristine (VCR) proportional to body weight (15 mg/kg/wk × 4 wks) have a poorer outcome than non-obese mice (event free survival: Obese = 0.42, Control = 0.75, p=0.07, log rank). The present study was designed to quantify the pharmacokinetic (PK) parameters of vincristine in control and obese mice and determine whether differences in these parameters could explain the poorer outcome in the obese mice. Twenty obese and 20 control mice received tail-vein injections of tritiated vincristine (specific activity 75 mCi/mg; dose 0.5 mg/kg). Blood samples were taken at 5 minutes, and the mice sacrificed at various time-points between 15 minutes and 24 hours post-injection. Whole blood and tissue specimens were solubilized, decolorized, and read on a scintillation counter. Blood vincristine concentrations were fit to a 3-compartment model using the two-stage PK in 3 subsets of VCR concentrations vs. time method. Non-compartmental modeling was used to confirm the results. Due to body weight differences, obese mice received ~ 28% more vincristine per injection than controls. Blood vincristine concentrations in both groups of animals followed a triexponential decay, as has been previously described. Blood levels tended to be higher (by 20±15%) in the obese mice at all time-points tested. While the t1/2α was longer in the obese mice (10.6 vs. 6.0 minutes), the t1/2b and t1/2γ were both shorter (22.7 vs. 27.1 minutes and 114.4 vs. 345.8 hours). Therefore the AUC0 → 24 was higher in the obese mice (3,279 vs. 2,776 ng/ml*hr), while the AUC0 → ∞ was lower in the obese mice (21,705 vs. 53,581 ng/ml*hr). Vincristine concentrations in spleen and bone marrow were similar at all time-points in the obese and control groups. In summary, obesity caused alterations in vincristine pharmacokinetics, characterized by longer initial half-life but shorter terminal half-lives. Thus, it is possible that the decreased AUC0 → ∞ contributed to the poorer outcome in this model. Despite this, blood and tissue concentrations of vincristine were equal or higher in the obese mice during the first 24 hours after injection of the drug when it was dosed proportional to body weight. These data suggest that dosing vincristine in obese patients based on body surface may lead to lower levels in blood and tissue, particularly if the dose is capped. As the prevalence of obesity continues to increase, pharmacokinetics studies should be performed in obese and lean subjects to further optimize chemotherapy dosing regimens in obese patients.

Influence of Hemorrhagic Shock on Remifentanil

2001 ◽  
Vol 94 (2) ◽  
pp. 322-332 ◽  
Author(s):  
Ken B. Johnson ◽  
Steven E. Kern ◽  
Elizabeth A. Hamber ◽  
Scott W. McJames ◽  
Katelijne M. Kohnstamm ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Time Course ◽  
Compartment Model ◽  
Central Compartment ◽  
Pharmacokinetic Parameters ◽  
Blood Levels ◽  
Maximal Effect ◽  
Spectral Edge ◽  
Target Plasma Concentration ◽  
The Impact

Background Hemorrhagic shock is known to alter significantly the pharmacokinetics of fentanyl, an opioid that requires delivery to the liver for metabolism. The authors hypothesized that the pharmacokinetics and pharmacodynamics of remifentanil, an esterase metabolized opioid that does not require delivery to a metabolic organ, would be altered less by hemorrhagic shock that those of fentanyl. Methods Sixteen pigs were assigned randomly to control and shock groups. The shock group was bled using an isobaric hemorrhage model. Remifentanil 10 microg x kg(-1) x min(-1) was infused for 10 min to both groups. Arterial samples were collected for remifentanil concentration assay. Pharmacokinetic parameters were estimated using a three-compartment model. The electroencephalogram spectral edge was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. Results Remifentanil blood levels were higher in the shocked group. The central clearance was slower and the central compartment was smaller in shocked animals. No difference between groups was observed in the magnitude or time course of the remifentanil-induced decrease in spectral edge. Conclusions Hemorrhagic shock altered the pharmacokinetics of remifentanil, suggesting that less remifentanil would be required to maintain a target plasma concentration. However, because of its rapid metabolism, the impact of hemorrhagic shock on the concentration decline of remifentanil after termination of the infusion was minimal. Hemorrhagic shock did not alter the pharmacodynamics of remifentanil.

scholarly journals Modeling the Autoinhibition of Clarithromycin Metabolism during Repeated Oral Administration

2009 ◽  
Vol 53 (7) ◽  
pp. 2892-2901 ◽  
Author(s):  
Khaled Abduljalil ◽  
Martina Kinzig ◽  
Jürgen Bulitta ◽  
Stefan Horkovics-Kovats ◽  
Fritz Sörgel ◽  
...  
Keyword(s):  
Oral Administration ◽  
Time Course ◽  
Standard Dose ◽  
Model Development ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Weibull Function ◽  
Time Profiles

ABSTRACT Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14(R)-hydroxy-clarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The pharmacokinetics of clarithromycin and its 14(R)-hydroxyl metabolite were adequately described by a one-compartment model each for clarithromycin and its metabolite as well as an inhibition compartment that reflects the autoinhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.

scholarly journals Urinary excretion and blood level of prions in scrapie-infected hamsters

2007 ◽  
Vol 88 (10) ◽  
pp. 2890-2898 ◽  
Author(s):  
Yuichi Murayama ◽  
Miyako Yoshioka ◽  
Hiroyuki Okada ◽  
Masuhiro Takata ◽  
Takashi Yokoyama ◽  
...  
Keyword(s):  
Oral Administration ◽  
Urinary Excretion ◽  
Time Course ◽  
Transmissible Spongiform Encephalopathy ◽  
Horizontal Transmission ◽  
Buffy Coat ◽  
High Rate ◽  
Disease Stage ◽  
Blood Levels ◽  
Spongiform Encephalopathy

Prions, infectious agents causing transmissible spongiform encephalopathy (TSE), are composed primarily of the pathogenic form (PrPSc) of the host-encoded prion protein. Although very low levels of infectivity have been detected in urine from scrapie-infected rodents, no reports of urinary PrPSc have been substantiated. Studies on the dynamics of urinary PrPSc during infection are needed to ensure the safety of urine-derived biopharmaceuticals and to assess the possible horizontal transmission of prion diseases. Using the protein misfolding cyclic amplification technique, a time-course study of urinary excretion and blood levels of PrPSc was performed in Sc237-infected hamsters and a high rate of PrPSc excretion was found during the terminal stage of the disease. Following oral administration, PrPSc was present in all buffy coat samples examined; it was also present in most of the plasma samples obtained from hamsters in the symptomatic stage. PrPSc was excreted in urine for a few days after oral administration; subsequently, urinary PrPSc was not detected until the terminal disease stage. These results represent the first biochemical detection of PrPSc in urine from TSE-infected animals.

Analgesic and Diuretic Activity of Curcuma xanthorrhiza

1970 ◽  
Vol 3 (1) ◽  
Author(s):  
MK Hassan Mahmood ◽  
Sitesh Chandra Bachar ◽  
Md Saiful Islam ◽  
Mohammad Shawkat Ali
Keyword(s):  
Body Weight ◽  
Acetic Acid ◽  
Oral Administration ◽  
Crude Extract ◽  
Methanol Extract ◽  
Test Sample ◽  
Diuretic Effect ◽  
Diuretic Activity ◽  
Curcuma Xanthorrhiza ◽  
Oral Doses

The methanol extract of the dried rhizomes of Curcuma xanthorrhiza Roxb. (Zingiberaceae) showed significant analgesic and diuretic activities on Swiss albino mice. Oral administration of the crude extract at doses of 150 and 300 mg/kg body weight, exhibited 33.2 and 50.5% inhibition of acetic acid induced writhing in mice, respectively. Similar oral doses of the extract produced a maximum of 1.24 and 1.45 diuretic activity after 2 and 1 h of the study, respectively. The diuretic effect of the extract started after 1 h at doses of 150 and 300 mg/kg body weight of mice. It was observed that the diuretic activity increased with increasing the concentration of the test sample. Key words: Curcuma xanthorrhiza, Analgesic activity, Diuretic activity. Dhaka Univ. J. Pharm. Sci. Vol.3(1-2) 2004 The full text is of this article is available at the Dhaka Univ. J. Pharm. Sci. website

Influence of stable iodine on the uptake of the thyroid – model vs. experiment

2001 ◽  
Vol 40 (01) ◽  
pp. 31-37 ◽  
Author(s):  
U. Wellner ◽  
E. Voth ◽  
H. Schicha ◽  
K. Weber
Keyword(s):  
Time Course ◽  
Compartment Model ◽  
The Body ◽  
Iodine Uptake ◽  
Model Calculations ◽  
Physiological Conditions ◽  
Iodine Supply ◽  
Predicted Values ◽  
The Individual ◽  
Stable Iodine

Summary Aim: The influence of physiological and pharmacological amounts of iodine on the uptake of radioiodine in the thyroid was examined in a 4-compartment model. This model allows equations to be derived describing the distribution of tracer iodine as a function of time. The aim of the study was to compare the predictions of the model with experimental data. Methods: Five euthyroid persons received stable iodine (200 μg, 10 mg). 1-123-uptake into the thyroid was measured with the Nal (Tl)-detector of a body counter under physiological conditions and after application of each dose of additional iodine. Actual measurements and predicted values were compared, taking into account the individual iodine supply as estimated from the thyroid uptake under physiological conditions and data from the literature. Results: Thyroid iodine uptake decreased from 80% under physiological conditions to 50% in individuals with very low iodine supply (15 μg/d) (n = 2). The uptake calculated from the model was 36%. Iodine uptake into the thyroid did not decrease in individuals with typical iodine supply, i.e. for Cologne 65-85 μg/d (n = 3). After application of 10 mg of stable iodine, uptake into the thyroid decreased in all individuals to about 5%, in accordance with the model calculations. Conclusion: Comparison of theoretical predictions with the measured values demonstrated that the model tested is well suited for describing the time course of iodine distribution and uptake within the body. It can now be used to study aspects of iodine metabolism relevant to the pharmacological administration of iodine which cannot be investigated experimentally in humans for ethical and technical reasons.

Evaluation of Glucose and Lipid Lowering Activity of Arganimide A in Normal and Streptozotocin-Induced Diabetic Rats

2019 ◽  
Vol 19 (4) ◽  
pp. 503-510 ◽  
Author(s):  
Mohamed Eddouks ◽  
Farid Khallouki ◽  
Robert W. Owen ◽  
Morad Hebi ◽  
Remy Burcelin
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Oral Administration ◽  
Lipid Profile ◽  
Plasma Cholesterol ◽  
Diabetic Rats ◽  
Lipid Lowering ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Lowering Activity

Aims: Arganimide A (4,4-dihydroxy-3,3-imino-di-benzoic acid) is a compound belonging to a family of aminophenolics found in fruit of Argania spinosa. The purpose of this study was to investigate the glucose and lipid lowering activity of Arganimide A (ARG A). Methods: The effect of a single dose and daily oral administration of Arganimide A (ARG A) on blood glucose levels and plasma lipid profile was tested in normal and streptozotocin (STZ) diabetic rats at a dose of 2 mg/kg body weight. Results: Single oral administration of ARG A reduced blood glucose levels from 26.50±0.61 mmol/L to 14.27±0.73 mmol/L (p<0.0001) six hours after administration in STZ diabetic rats. Furthermore, blood glucose levels were decreased from 5.35±0.30 mmol/L to 3.57±0.17 mmol/L (p<0.0001) and from 26.50±0.61 mmol/L to 3.67±0.29 mmol/L (p<0.0001) in normal and STZ diabetic rats, respectively, after seven days of treatment. Moreover, no significant changes in body weight in normal and STZ rats were shown. According to the lipid profile, the plasma triglycerides levels were decreased significantly in diabetic rats after seven days of ARG treatment (p<0.05). Moreover, seven days of ARG A treatment decreased significantly the plasma cholesterol concentrations (p<0.001). Conclusion: ARG A possesses glucose and lipid-lowering activity in diabetic rats and this natural compound may be beneficial in the treatment of diabetes.

DIFFERENT EFFECTS OF ORAL DOSES OF TRIIODOTHYRONINE OR THYROXINE ON THE INHIBITION OF THYROTROPHIN RELEASING HORMONE (TRH) MEDIATED THYROTROPHIN (TSH) RESPONSE IN MAN

1975 ◽  
Vol 80 (1) ◽  
pp. 42-48 ◽  
Author(s):  
K. W. Wenzel ◽  
H. Meinhold ◽  
H. Schleusener
Keyword(s):  
Oral Administration ◽  
Binding Sites ◽  
Direct Action ◽  
Normal Range ◽  
Thyrotrophin Releasing Hormone ◽  
Releasing Hormone ◽  
Pituitary Tissue ◽  
Tsh Secretion ◽  
Inhibiting Protein ◽  
Oral Doses

ABSTRACT Since contradicting results about the existence of T3 or T3 and T4 receptors in pituitary tissue have been reported, the influence of L-triiodothyronine (L-T3) or L-thyroxine (L-T4) on TRH stimulated TSH release was investigated. Oral administration of 50 μg L-T3 caused an increasing inhibition of TSH response to 400 μg TRH from 64 % 2 h after L-T3 intake to 29% after 24 h, while serum T3 peaks up to 5.45 ng/ml occurred between 2 to 4 h after L-T3 ingestion and became normal after 8 to 10 h. This delay in the T3 action on TRH inhibition agrees with the postulate that T3 induces the synthesis of an inhibiting protein which is blocking TSH liberation. Oral administration of 1000 μg L-T4 induced increments of serum T4 up to 221 ng/ml between 6 to 24 h after intake; however, a TRH inhibition of 62 % did not become evident before 48 h. At this time T3 levels had risen to the upper normal range. These results support the theory that T3 is responsible for the regulation of TSH secretion. An intra-pituitary conversion from T4 to T3 seems more likely the cause of the TRH inhibition rather than the peripheral T4-T3 conversion or a direct action by T4 binding sites in the pituitary.

Serum Levels of Melatonin in Cancer Patients and their Relation to Body Sizes

1988 ◽  
Vol 3 (3) ◽  
pp. 193-196 ◽  
Author(s):  
S. Barni ◽  
P. Lissoni ◽  
S. Crispino ◽  
F. Rovelli ◽  
G. Esposti ◽  
...  
Keyword(s):  
Body Weight ◽  
Body Size ◽  
Cancer Patients ◽  
Serum Levels ◽  
Blood Levels ◽  
Melatonin Secretion ◽  
Normal Range ◽  
Blood Concentrations ◽  
Patients With Cancer ◽  
Body Sizes

Melatonin secretion is often enhanced in patients with cancer. In the light of a reported correlation between melatonin levels and body size, we investigated blood levels of this pineal hormone in a group of 72 patients affected by cancer, 30 of whom had body weight within the normal range, 30 were obese and the last 12 cases had body weight below the normal range, in order to establish whether in fact melatonin blood concentrations were related to body size. Melatonin levels were high in 19/72 patients (26%). The mean levels of the pineal hormone were similar in patients with normal, low and high body weight. Finally, there was no significant correlation between melatonin values and body weight, height or surface. Melatonin secretion thus does not appear to be influenced by body size in cancer patients.

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