Influence of cimetidine on the toxicity and toxicokinetics of diazinon in the rat

1996 ◽  
Vol 15 (5) ◽  
pp. 391-395 ◽  
Author(s):  
HX Wu ◽  
CI Evreux-Gros ◽  
J. Descotes
Keyword(s):  
Wistar Rats ◽  
Total Body Clearance ◽  
Systemic Circulation ◽  
Time Curve ◽  
Concentration Time ◽  
Male Wistar Rats ◽  
Total Body ◽  
The Brain ◽  
Brain Acetylcholinesterase ◽  
Body Clearance

1 The influence of cimetidine on diazinon toxicity and toxicokinetics was investigated in male Wistar rats. 2 The acute toxicity of diazinon, as well as brain acetylcholinesterase and carboxylesterase inhibition, were potentiated by pretreating rats with cimetidine (80 mg kg-1, ip) 1 and 24 h prior to diazinon applica tion (50 mg kg-1, i.p.). 3 Comparison of toxicokinetic parameters between control and cimetidine-treated animals, showed a significant decrease in diazinon total body clearance and a marked increase in the area under the plasma concentration-time curve following cimetidine. 4 These results indicate that a major cause of the potentiation of diazinon may be related to the increase in the amount of diazinon in the systemic circulation as well as in the brain.

scholarly journals Pharmacokinetic evaluation of the interaction between oral kaempferol and ethanol in rats

2016 ◽  
Vol 66 (4) ◽  
pp. 563-568 ◽  
Author(s):  
Zhaoxiang Zhou ◽  
Meng Wang ◽  
Zengjun Guo ◽  
Xiaoying Zhang
Keyword(s):  
Oral Bioavailability ◽  
High Performance ◽  
Total Body Clearance ◽  
Control Groups ◽  
Oral Gavage ◽  
Time Curve ◽  
Concentration Time ◽  
Oral Control ◽  
Total Body ◽  
Body Clearance

Abstract This study was aimed at investigating the effect of ethanol on oral bioavailability of kaempferol in rats, namely, at disclosing their possible interaction. Kaempferol (100 or 250 mg kg-1 bm) was administered to the rats by oral gavage with or without ethanol (600 mg kg-1 bm) co-administration. Intravenous administration (10 and 25 mg kg-1 bm) of kaempferol was used to determine the bioavailability. The concentration of kaempferol in plasma was estimated by ultra high performance liquid chromatography. During coadministration, a significant increase of the area under the plasma concentration-time curve as well as the peak concentration were observed, along with a dramatic decrease in total body clearance. Consequently, the bioavailability of kaempferol in oral control groups was 3.1 % (100 mg kg-1 bm) and 2.1 % (250 mg kg-1 bm). The first was increased by 4.3 % and the other by 2.8 % during ethanol co-administration. Increased permeability of cell membrane and ethanolkaempferol interactions on CYP450 enzymes may enhance the oral bioavailability of kaempferol in rats.

scholarly journals Pharmacokinetics of a New Parenteral Oligosaccharide Antibiotic, SCH27899 (Ziracin), in Healthy Subjects

2001 ◽  
Vol 45 (3) ◽  
pp. 917-921 ◽  
Author(s):  
Osamu Kozawa ◽  
Toshihiko Uematsu ◽  
Hiroyuki Matsuno ◽  
Masayuki Niwa ◽  
Ken-Ichi Kohno ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Moderate Degree ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Japanese Male ◽  
Pharmacokinetic Properties ◽  
Repeated Doses ◽  
Total Body ◽  
Body Clearance

ABSTRACT The pharmacokinetic properties of an everninomicin antibiotic (SCH27899; Ziracin) were studied with healthy Japanese male volunteers by single (1, 3, 6, and 9 mg/kg of body weight) and multiple 60-min intravenous infusions (3, 6, and 9 mg/kg once daily for 10 consecutive days following a 2-day interval after the initial dose). At single doses the peak serum concentration and the area under the serum concentration-time curve linearly increased with the dose. While total body clearance (CL; 31.2 to 45.6 ml/kg/h) and percent cumulative urinary recovery as unchanged drug (4.9 to 7.1%) were rather constant irrespective of doses, the terminal half-life of γ phase (t 1/2γ; 14.2 to 19.6 h) were slightly prolonged at the higher two doses compared with the lower two doses. With repeated doses of SCH27899, a statistically significant decrease and increase were found in CL and t 1/2γ of about 36 and 21%, respectively, although these changes may be clinically irrelevant. The most commonly reported adverse events were local reactions such as erythema, pain, and palpable venous cord of mild to moderate degree around the injection site, which could be managed by changing the injection sites.

scholarly journals Pharmacokinetics of Intravenous Piperacillin Administration in Patients Undergoing On-Line Hemodiafiltration

2009 ◽  
Vol 53 (8) ◽  
pp. 3266-3268 ◽  
Author(s):  
Kook-Hwan Oh ◽  
Chiweon Kim ◽  
Hankyu Lee ◽  
Hajeong Lee ◽  
Ji Yong Jung ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Total Body Clearance ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Recovery Method ◽  
Elimination Half ◽  
On Line ◽  
The Mean ◽  
Total Body ◽  
Body Clearance

ABSTRACT The pharmacokinetic characteristics of piperacillin sodium were studied in five volunteers undergoing on-line hemodiafiltration (HDF). The subjects were given 2 g of piperacillin sodium intravenously over 1 min and placed on on-line HDF for 4 h starting at 60 min after the piperacillin infusion. Noncompartmental models were employed for estimation of the pharmacokinetic parameters, and intradialytic piperacillin clearance was calculated by the recovery method. The mean volume of distribution and the elimination half-life were 0.27 ± 0.13 liter/kg (mean ± standard deviation) and 1.1 ± 0.6 h, respectively. The total body clearance of piperacillin was 0.19 ± 0.08 liter/h/kg. Piperacillin clearance through on-line HDF was 0.11 ± 0.06 liter/h/kg. The mean serum piperacillin concentration was 4.0 ± 1.9 μg/ml at the end of the 4-h on-line HDF session. The concentration of infused piperacillin recovered in the dialysate was 527 ± 236 mg (26.3% ± 11.8%). We suggest the replacement of 500 mg of piperacillin after each on-line HDF session.

scholarly journals Slower Elimination of Tofacitinib in Acute Renal Failure Rat Models: Contribution of Hepatic Metabolism and Renal Excretion

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 714
Author(s):  
Sung Hun Bae ◽  
Sun-Young Chang ◽  
So Hee Kim
Keyword(s):  
Rheumatoid Arthritis ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Hepatic Metabolism ◽  
Term Treatment ◽  
Concentration Time ◽  
Long Term Treatment ◽  
Total Body ◽  
Body Clearance

Tofacitinib is a Jak inhibitor developed as a treatment for rheumatoid arthritis. Tofacitinib is metabolized mainly through hepatic CYP3A1/2, followed by CYP2C11. Rheumatoid arthritis tends to increase renal toxicity due to drugs used for long-term treatment. In this study, pharmacokinetic changes of tofacitinib were evaluated in rats with gentamicin (G-ARF) and cisplatin-induced acute renal failure (C-ARF). The time-averaged total body clearance (CL) of tofacitinib in G-ARF and C-ARF rats after 1-min intravenous infusion of 10 mg/kg was significantly decreased by 37.7 and 62.3%, respectively, compared to in control rats. This seems to be because the time-averaged renal clearance (CLR) was significantly lower by 69.5 and 98.6%, respectively, due to decreased creatinine clearance (CLCR). In addition, the time-averaged nonrenal clearance (CLNR) was also significantly lower by 33.2 and 57.4%, respectively, due to reduction in the hepatic CYP3A1/2 and CYP2C11 subfamily in G-ARF and C-ARF rats. After oral administration of tofacitinib (20 mg/kg) to G-ARF and C-ARF rats, both CLR and CLNR were also significantly decreased. In conclusion, an increase in area under plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib in G-ARF and C-ARF rats was due to the significantly slower elimination of tofacitinib contributed by slower hepatic metabolism and urinary excretion of the drug.

Hepatomesenteric release and removal of norepinephrine in swine

1995 ◽  
Vol 268 (4) ◽  
pp. R924-R930 ◽  
Author(s):  
A. Aneman ◽  
G. Eisenhofer ◽  
L. Fandriks ◽  
P. Friberg
Keyword(s):  
Total Body Clearance ◽  
Splanchnic Nerve ◽  
Neuronal Uptake ◽  
Blocking Drug ◽  
Hepatic Extraction ◽  
Valid Assessment ◽  
Total Body ◽  
Splanchnic Nerve Stimulation ◽  
Body Clearance ◽  
Venous Plasma

Release and removal of norepinephrine (NE) by hepatomesenteric organs in anesthetized swine were examined using measurements of NE in arterial, portal, and hepatic venous plasma. NE spillover from the liver and mesenteric organs increased during splanchnic nerve stimulation, validating these measurements as indexes of sympathetic outflow. Administration of the neuronal uptake-blocking drug desipramine reduced mesenteric NE extraction more than hepatic extraction, suggesting that neuronal uptake was more important for NE removal in mesenteric organs than in the liver. Circulating NE was removed by the liver more efficiently than by mesenteric organs, whereas mesenteric NE spillover (2.46 nmol/min) exceeded liver NE spillover (0.74 nmol/min). Hepatomesenteric NE spillover represented 53% of total body spillover; NE clearance was 42% of total body clearance. Because of efficient hepatic extraction of NE released by mesenteric organs, the sum of mesenteric and hepatic NE spillovers (3.20 pmol/min) exceeded net hepatomesenteric spillover estimated using arterial and hepatic venous measurements alone (1.96 pmol/min). Thus valid assessment of the substantial amounts of NE released by hepatomesenteric organs requires separate examination of mesenteric and hepatic spillovers.

Model of spontaneous obesity in aging male Wistar rats

1990 ◽  
Vol 259 (6) ◽  
pp. R1117-R1125 ◽  
Author(s):  
F. D. Newby ◽  
M. DiGirolamo ◽  
G. A. Cotsonis ◽  
M. H. Kutner
Keyword(s):  
Body Weight ◽  
Lipid Content ◽  
Wistar Rats ◽  
Lipid A ◽  
Curvilinear Relationship ◽  
Body Lipid ◽  
Fat Depots ◽  
Male Wistar Rats ◽  
Total Body ◽  
Relationship Of

We analyzed retrospectively data from 148 chow-fed male Wistar rats killed between the age of 6 wk and 2 yr while varying in body weight from 136 to 917 g. The purpose of this study was to clarify the relationship of body weight and body lipid content with the composition and cellularity of the epididymal and retroperitoneal fat depots. A positive linear association was found between body weight and body water or fat-free dry residue, whereas total body lipid exhibited a curvilinear relationship with body weight. The weight of the epididymal pads was linearly related to body weight but not to body lipid. In contrast, retroperitoneal pad weight was exponentially related to body weight and paralleled total body lipid. A strong linear correlation was found between total body lipid and weight (r = 0.959) or depot lipid content (r = 0.967) of the retroperitoneal fat pads. In this rat model of aging and spontaneous obesity, significant regional differences exist in adipose depot composition and cellularity. A practical outcome of this study is a simple and accurate prediction of body lipid content from the gravimetric determination of the retroperitoneal fat depots.

scholarly journals β-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Alexandra Jacobs ◽  
Fabio Silvio Taccone ◽  
Jason A. Roberts ◽  
Frédérique Jacobs ◽  
Frederic Cotton ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Renal Clearance ◽  
Total Body Clearance ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Augmented Renal Clearance ◽  
Drug Concentrations ◽  
Trough Concentrations ◽  
Total Body ◽  
Body Clearance

ABSTRACTAugmented renal clearance is commonly observed in septic patients and may result in insufficient β-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of β-lactam antibiotics and measured creatinine clearance and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients who had a measured creatinine clearance of ≥120 ml/min and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime, or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic (PK) analysis of the data was performed using the Pmetrics software package for R. Fifty-five percent of drug concentrations showed insufficient β-lactam serum concentrations to treat infections due toPseudomonas aeruginosa. There were significant, yet weak, correlations between measured creatinine clearance and trough concentrations of meropenem (r= −0.21,P= 0.01), trough concentrations of piperacillin (r= −0.28,P= 0.0071), concentrations at 50% of the dosage interval (r= −0.41,P< 0.0001), and total body clearance of piperacillin (r= 0.39,P= 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem but not for piperacillin. Therefore, specific PK modeling can predict certain β-lactam concentrations based on renal function but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens.

Human plasma pharmacokinetics of thiotepa following administration of high-dose thiotepa and cyclophosphamide.

1988 ◽  
Vol 6 (7) ◽  
pp. 1192-1196 ◽  
Author(s):  
S P Ackland ◽  
K E Choi ◽  
M J Ratain ◽  
M J Egorin ◽  
S F Williams ◽  
...  
Keyword(s):  
Stepwise Regression ◽  
Total Body Clearance ◽  
Linear Functions ◽  
High Dose ◽  
Metabolic Clearance ◽  
Plasma Decay ◽  
Plasma Pharmacokinetics ◽  
Total Body ◽  
Dose Dependent ◽  
Body Clearance

Thiotepa is an established alkylating agent whose pharmacokinetics in standard doses are well defined. In order to ascertain whether dose-dependent variations in pharmacokinetics occur, we have undertaken an analysis of plasma thiotepa levels in 16 patients entered on a phase I-II study of bialkylator chemotherapy. High-dose thiotepa (1.8 to 7.0 mg/kg) and cyclophosphamide (2.5 g/m2) were administered intravenously (IV) on days -6, -4, and -2 followed by autologous marrow reinfusion on day 0. Plasma and urinary thiotepa was assayed by gas chromatography. Biexponential plasma decay curves were seen in ten patients, with a t 1/2 alpha of 10.0 +/- 6.4 minutes, a t 1/2 beta of 174 +/- 61 minutes and a total body clearance of 379 +/- 153 mL/h/kg (mean +/- SD). Six patients displayed monoexponential plasma decay curves with a terminal t 1/2 of 137 +/- 83 minutes and a total body clearance of 440 +/- 195 mL/h/kg. Although there was a trend toward reduced plasma clearance in the three patients treated at the highest dose level, the available data suggest that metabolic clearance mechanisms for thiotepa were not saturated with the doses used in this study. By stepwise regression analysis, linear functions using only 15-minute and four-hour postinfusion plasma levels were derived that correlated closely with area under the plasma concentration X time curves (AUC) (P less than .002). We conclude that high-dose thiotepa results in similar pharmacokinetic values to conventional doses with no apparent dose-dependent variation. The value of specific time points to predict AUC and clearance will require prospective evaluation.

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