Drug Pharmacokinetics Following a Single IV Bolus Administration: Drug Clearance

2012 ◽  
pp. 74-83
Keyword(s):  
Drug Clearance ◽  
Bolus Administration ◽  
Drug Pharmacokinetics

scholarly journals Optimizing Antimicrobial Drug Dosing in Critically Ill Patients

2021 ◽  
Vol 9 (7) ◽  
pp. 1401
Author(s):  
Pedro Póvoa ◽  
Patrícia Moniz ◽  
João Gonçalves Pereira ◽  
Luís Coelho
Keyword(s):  
Critically Ill ◽  
Antimicrobial Therapy ◽  
Critically Ill Patients ◽  
Pathogen Resistance ◽  
Volume Of Distribution ◽  
Drug Clearance ◽  
Therapeutic Drug ◽  
Drug Dosing ◽  
Sepsis And Septic Shock ◽  
Drug Pharmacokinetics

A fundamental step in the successful management of sepsis and septic shock is early empiric antimicrobial therapy. However, for this to be effective, several decisions must be addressed simultaneously: (1) antimicrobial choices should be adequate, covering the most probable pathogens; (2) they should be administered in the appropriate dose, (3) by the correct route, and (4) using the correct mode of administration to achieve successful concentration at the infection site. In critically ill patients, antimicrobial dosing is a common challenge and a frequent source of errors, since these patients present deranged pharmacokinetics, namely increased volume of distribution and altered drug clearance, which either increased or decreased. Moreover, the clinical condition of these patients changes markedly over time, either improving or deteriorating. The consequent impact on drug pharmacokinetics further complicates the selection of correct drug schedules and dosing during the course of therapy. In recent years, the knowledge of pharmacokinetics and pharmacodynamics, drug dosing, therapeutic drug monitoring, and antimicrobial resistance in the critically ill patients has greatly improved, fostering strategies to optimize therapeutic efficacy and to reduce toxicity and adverse events. Nonetheless, delivering adequate and appropriate antimicrobial therapy is still a challenge, since pathogen resistance continues to rise, and new therapeutic agents remain scarce. We aim to review the available literature to assess the challenges, impact, and tools to optimize individualization of antimicrobial dosing to maximize exposure and effectiveness in critically ill patients.

scholarly journals Initial Concentration-Time Profile of Gentamicin Determines Efficacy against Enterobacter cloacae ATCC 13047

1998 ◽  
Vol 42 (6) ◽  
pp. 1370-1374 ◽  
Author(s):  
Craig R. Rayner ◽  
Lisa L. Ioannides-Demos ◽  
Jo-Anne E. Brien ◽  
Lisa L. Liolios ◽  
W. John Spicer
Keyword(s):  
Trough Concentration ◽  
Enterobacter Cloacae ◽  
Bactericidal Effect ◽  
Drug Clearance ◽  
Bolus Administration ◽  
Bacterial Killing ◽  
Initial Exposure ◽  
Concentration Time ◽  
Bactericidal Effects

ABSTRACT In vitro studies were designed to investigate the influence of peak drug concentration (C max), the area under the concentration-time curve (AUC), and, consequently, the trough concentration on the bactericidal effects of gentamicin againstEnterobacter cloacae (MIC, 0.5 mg/liter) by simulating bolus versus infusion administration and bolus dosing with altered drug clearance. Bacteria in the lag phase were exposed to gentamicin concentration-time profiles modelling either bolus or infusion dosing (AUC constant, C max changing) with 30-min postdose peak concentrations (C peak30) of 4, 6, 8, and 10 mg/liter or bolus dosing with normal and double drug clearance (C max constant, AUC changing) corresponding to normal clearance profiles withC peak30 of 6 and 8 mg/liter. Exposure to gentamicin caused early bactericidal effects apparent by 2 h, followed by variable bacteriostatic and recovery phases. Exposure to bolus profiles resulted in greater bactericidal activity than the corresponding infusion profile up to a C peak30of 8 mg/liter. At a C peak30 of 10 mg/liter, there were no differences in bactericidal effect. Double clearance profiles had a reduced bactericidal effect at 6 mg/liter compared to the corresponding normal clearance profile, but no differences in bactericidal effect were observed for 8-mg/liter double and normal clearance profiles. These results suggest that the initial exposure (i.e., 0 to 30 min) is a more important determinant for bacterial killing than the AUC or trough concentration for this bacterium. Subject to confirmation of these findings with other gram-negative bacteria, to optimize aminoglycoside efficacy the initial exposure (C max) should be maximized by giving higher doses or bolus administration at intervals which may not produce detectable trough concentrations. Clinical trials with a broad range of patients, especially those with higher clearance, would confirm these in vitro observations and define optimal dosing recommendations.

In vitro strategy to quantify changes in hepatobiliary drug clearance by herbal extracts

Planta Medica ◽  
2014 ◽  
Vol 80 (10) ◽  
Author(s):  
JP Jackson ◽  
K Freeman ◽  
J Hatfield ◽  
B St Claire ◽  
C Hubert ◽  
...  
Keyword(s):  
Drug Clearance ◽  
Herbal Extracts

Replacement of oxytocin bolus administration by infusion: influences on adverse postpartum outcome

2014 ◽  
Vol 74 (S 01) ◽  
Author(s):  
JJ Löytved-Hardegg ◽  
M Brunner ◽  
JJ Ries ◽  
S von Felten ◽  
C Heugel ◽  
...  
Keyword(s):  
Bolus Administration

Fibrin-specificity of a Plasminogen Activator Affects the Efficiency of Fibrinolysis and Responsiveness to Ultrasound: Comparison of Nine Plasminogen Activators In Vitro

1999 ◽  
Vol 81 (04) ◽  
pp. 605-612 ◽  
Author(s):  
Dmitry V. Sakharov ◽  
Marrie Barrett-Bergshoeff ◽  
Rob T. Hekkenberg ◽  
Dingeman C. Rijken
Keyword(s):  
Thrombolytic Therapy ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Bolus Administration ◽  
High Frequency Ultrasound ◽  
Single Chain ◽  
Response Curves ◽  
Maximal Speed ◽  
Frequency Ultrasound

SummaryIn a number of cases, thrombolytic therapy fails to re-open occluded blood vessels, possibly due to the occurrence of thrombi resistant to lysis. We investigated in vitro how the lysis of hardly lysable model thrombi depends on the choice of the plasminogen activator (PA) and is accelerated by ultrasonic irradiation. Lysis of compacted crosslinked human plasma clots was measured after addition of nine different PAs to the surrounding plasma and the effect of 3 MHz ultrasound on the speed of lysis was assessed.Fibrin-specific PAs showed bell-shaped dose-response curves of varying width and height. PAs with improved fibrin-specificity (staphylokinase, the TNK variant of tissue-type PA [tPA], and the PA from the saliva of the Desmodus rotundus bat) induced rapid lysis in concentration ranges (80-, 260-, and 3,500-fold ranges, respectively) much wider than that for tPA (a 35-fold range). However, in terms of speed of lysis, these three PAs exceeded tPA only slightly. Reteplase and single-chain urokinase were comparable to tPA, whereas two-chain urokinase, anistreplase, and streptokinase were inferior to tPA. In the case of fibrin-specific PAs, ultrasonic treatment accelerated lysis about 1.5-fold. For streptokinase no acceleration was observed. The effect of ultrasound correlated with the presence of plasminogen in the outer plasma, suggesting that it was mediated by facilitating the transport of plasminogen to the surface of the clot.In conclusion, PAs with improved fibrin-specificity induce rapid lysis of plasminogen-poor compacted plasma clots in much wider concentration ranges than tPA. This offers a possibility of using single-or double-bolus administration regimens for such PAs. However, it is not likely that administration of these PAs will directly cause a dramatic increase in the rate of re-opening of the occluded arteries since they are only moderately superior to tPA in terms of maximal speed of lysis. Application of high-frequency ultrasound as an adjunct to thrombolytic therapy may increase the treatment efficiency, particularly in conjunction with fibrin-specific PAs.

Combination of Antibiotic Treatment with the Thrombin Inhibitor Recombinant Hirudin for the Therapy of Experimental Klebsiella pneumoniae Sepsis

1994 ◽  
Vol 71 (06) ◽  
pp. 768-772 ◽  
Author(s):  
Gerhard Dickneite ◽  
Jörg Czech
Keyword(s):  
Septic Shock ◽  
Klebsiella Pneumoniae ◽  
Organ Failure ◽  
Therapeutic Effect ◽  
Disseminated Intravascular Coagulation ◽  
Post Infection ◽  
Thrombin Inhibitor ◽  
Bolus Administration ◽  
Bacterial Burden ◽  
Recombinant Hirudin

SummaryRats which were infected with the gramnegative pathogen Klebsiella pneumoniae develop disseminated intravascular coagulation (DIC), multi-organ failure (MOF) and finally die in a septic shock. We investigated the therapeutic effect of antibiotic (tobramycin) treatment combined with the infusion of the highly specific thrombin inhibitor rec. hirudin. Although administration of 2 mg/kg tobramycin alone leads to a decrease of the bacterial burden, DIC could not be prevented. Infusion of rec. hirudin (0.25 mg/kg x h) for 4 h (start of treatment 1 h post infection), in addition to a bolus administration of tobramycin, led to an amelioration of DIC parameters as fibrinogen, thrombin-antithrombin complex (TAT) and platelets. Serum transaminase levels (GOT, GPT) as a marker of MOF were significantly improved by rec. hirudin, the T50 value increased from 17 h in the tobramycin group to 42 h in the tobramycin + rec. hirudin giuup, muilality rates were 90% or 60%, respectively. Combination of heparin (10011/kg x h) and tobramycin was not effective on survival.

Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics

2019 ◽  
Vol 26 (7) ◽  
pp. 1185-1223 ◽  
Author(s):  
Carolina I. Ghanem ◽  
Jose E. Manautou
Keyword(s):  
Abc Transporters ◽  
Basolateral Membrane ◽  
Clinical Use ◽  
Nucleotide Analogs ◽  
Synthetic Drugs ◽  
The Family ◽  
Hepatic Transporter ◽  
Related Proteins ◽  
Drug Pharmacokinetics ◽  
Conjugated Metabolites

Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.

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