influence of renal and hepatic disease on pharmacokinetics pdf

Influence Of Renal And Hepatic Disease On Pharmacokinetics Pdf

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Inhibition and induction of drug-metabolizing enzymes are the most frequent and dangerous drug-drug interactions. They are an important cause of serious adverse events that have often resulted in early termination of drug development or withdrawal of drugs from the market. Management of such interactions by dose adjustment in clinical practice is extremely difficult because of the wide interindividual variability in their magnitude.

Liver disease can modify the kinetics of drugs biotransformed by the liver. This review updates recent developments in this field, with particular emphasis on cytochrome P CYP.

Effects of Liver Disease on Pharmacokinetics

Wright Assistant Professor of Anesthesia. Szenohradszky Assistant Professor of Anesthesia. Because renal function affects the elimination of muscle relaxants, each new muscle relaxant must be evaluated in patients with renal failure. Accordingly, the neuromuscular effects and pharmacokinetics of rapacuronium were identified in patients with renal failure. Rapacuronium 1.

The adductor pollicis muscle twitch tension was monitored. Plasma samples were obtained frequently for a period of 8 h to measure the concentrations of ORG and its metabolite, ORG Pharmacokinetic parameters were determined using mixed-effects modeling.

One patient was excluded from analysis because he was taking phenytoin chronically. The neuromuscular effects of a single dose of rapacuronium are affected minimally by renal failure. However, the decreased clearance of rapacuronium and its potent metabolite in renal failure suggests that repeated dosing of rapacuronium may lead to prolonged effects in patients with renal failure.

Orange, NJ, and Organon Teknika, Boxtel, the Netherlands , a new nondepolarizing muscle relaxant, has a rapid onset, possibly comparable to that of succinylcholine, and that recovery after a bolus dose is more rapid than that of other nondepolarizing muscle relaxants.

In the current study, we administered a single dose of rapacuronium to patients with renal failure and to healthy volunteers to determine its neuromuscular and cardiovascular effects and its pharmacokinetic characteristics. We selected patients with renal failure who underwent non-transplant surgery to eliminate the possibility that a newly transplanted kidney might eliminate rapacuronium and thus confound our analyses. After obtaining approval from our local institutional review board and informed consent from each participant, we studied 10 healthy paid volunteers classified as American Society of Anesthesiologists physical status 1 and 10 patients with chronic renal failure Table 1.

Because of the concern that phenytoin might influence the pharmacokinetics, the neuromuscular effects of rapacuronium, or both, [9] data from that patient are reported separately and are not included in any neuromuscular or pharmacokinetic comparisons.

The volunteers and remaining patients were not taking any other drugs that might have influenced the neuromuscular response to rapacuronium. After an 8-h fast, an intravenous catheter was placed in an upper extremity of the volunteers and patients. Patients received premedication with mg midazolam. Anesthesia was maintained with propofol infused at approximately [micro sign]g [middle dot] kg -1 [middle dot] min If needed for clinical purposes e.

An intravenous catheter was placed in the contralateral arm or in the external jugular vein to sample blood. Ventilation was controlled to maintain normocapnia end-tidal carbon dioxide tension of mmHg. The esophageal temperature was maintained at more than 36 [degree sign]C by forced-air warming.

Except for two volunteers, arterial blood pressure Dinamapp; Critikon, Tampa, FL , heart rate, pulse oximetry N; Nellcor, Hayward, CA , and end-tidal carbon dioxide tension Ultima; Datex, Helsinki, Finland were recorded before and every minute for 5 min after rapacuronium administration, then every 5 min for 25 min.

Cutaneous signs of histamine release were sought and the lungs were auscultated regularly to check for wheezing. After loss of consciousness, a single 5-s Hz supramaximal tetanic stimulus [10] was applied to the ulnar nerve via subcutaneous gauge needles placed at the wrist followed by supramaximal train-of-four TOF stimuli every 12 s. The mechanical twitch response of the adductor pollicis muscle was measured with a calibrated force displacement transducer and amplified.

Twitch tension was digitized, displayed, and recorded on-line. Evoked twitch tension was also recorded on a strip chart. The first twitch response of each TOF T1 was stable for more than 5 min before rapacuronium was administered. The ratio of the fourth component to the first component of each TOF was determined. In volunteers and six patients, neuromuscular function was recorded until T1 recovered completely and the TOF ratio was more than 0.

Venous blood 5 ml was sampled before and 3, 7, 10, 20, 30, 45, 60, 75, 90, , , , , , , , , and min after rapacuronium administration. Except for samples obtained more than 2 h after administration of rapacuronium, all blood samples were obtained during a period of less than 10 s; the midpoint of the sampling interval was recorded.

For healthy volunteers, urine voided spontaneously was collected during the following time periods after rapacuronium administration: , , , , , , , and h. The patients were anuric. Sodium dihydrogen phosphate was added immediately to blood and urine samples to prevent rapacuronium degradation.

Blood was centrifuged within 30 min of sampling, and plasma and urine were stored at [degree sign]C. We simultaneously analyzed plasma or urine concentration values for all participants to determine typical values for the pharmacokinetic parameters, standard errors of these estimates, and interindividual variability see appendix 1.

In addition, we determined the influence of renal function and other covariates e. For rapacuronium, two-compartment models included the parameters clearance Cl , distributional clearance Cl distribution , and volumes of the central and peripheral compartments V 1 and V 2 , respectively. Three-compartment models included, in addition, a slow distributional clearance Cl slow and volume of the deep peripheral compartment V 3.

Assumptions used in this modeling are described in appendix 1. For ORG, one-compartment models included the parameters clearance Cl and volume of distribution V. Two-compartment models included the parameters clearance Cl , distributional clearance Cl distribution , and volumes of the central and peripheral compartments V 1 and V 2 , respectively. Three-compartment models included the additional parameters slow distributional clearance Cl slow and volume of the deep peripheral compartment V 3.

Assumptions used in these models are described in appendix 1. Because urinary recovery of the administered dose of rapacuronium as either rapacuronium or ORG was not complete, we could not estimate the fraction of the administered dose of rapacuronium that converted to ORG f metabolized. In turn, we could not estimate the volume of distribution and clearances for ORG; instead, all distribution volumes and clearances for ORG are normalized using f metabolized. However, because the shape of the plasma concentration versus the time curve for ORG is well described, half-life values for ORG are estimated accurately.

All analyses were performed using a model-building approach. Initially, patients with renal failure were assumed to have the same pharmacokinetic parameters as healthy volunteers. Two- and three-compartment models, weight-normalized and non-weight-normalized, were compared to determine the appropriate structural model.

The appropriateness of the error model was determined appendix 1. This Bayesian step determines the parameter estimates for each individual compared with the population estimates.

We plotted the resulting values for [Greek small letter eta] against the covariates age, weight, height, gender, group renal failures vs.

After we added a smoother lowess, a local regression to each plot, trends were sought by visual inspection. If we observed a relation between a pharmacokinetic parameter and a covariate, we tested this relation in the model.

We calculated half-lives using standard formulas; for three-compartment models, we calculated half-lives iteratively. Values for patients with renal failure were compared with those from healthy volunteers using the Mann-Whitney U test or the Student's t test for unpaired data.

For each group, values for heart rate and systolic, diastolic, and mean blood pressures were analyzed using repeated measures analysis of variance and Dunnett's test.

Twitch depression at 1 min was less in patients than in volunteers. Table 2. Plasma concentrations of rapacuronium initially decreased rapidly in both groups Figure 1.

After approximately 60 min, rapacuronium's plasma concentration decreased more slowly in patients with renal failure than in healthy volunteers. For rapacuronium, a three-compartment model was preferred to a two-compartment model Table 3 , models 3 and 4 compared with models 1 and 2 , weight normalization improved the objective function models 2 and 4 , and the constant coefficient of error model yielded fits comparable to the error model with two components model 4 vs.

Permitting the clearance value to differ between the groups markedly improved the quality of the fit model 6 vs. However, permitting interindividual variability to differ for each of V 2 and V 3 did improve the quality of the fit model 9 vs. Permitting each of V 2 model 10 vs. Permitting clearance to vary with age and V 3 to differ with gender also improved the quality of the fit models 12 and 13 vs.

Figure 1. Values for the plasma concentration of rapacuronium after administration of 1. Values for the patient who received phenytoin before anesthesia are shown with a dashed line. Thus the optimal model Table 4 , Figure 2 for rapacuronium had three compartments, and all pharmacokinetic parameters were weight normalized.

In both groups, clearance decreased 0. In healthy controls, clearance decreased from Half-lives varied as a function of renal function, age, and gender. There were no relations between the pharmacokinetic parameters and other covariates. However, fixing the parameter estimate for the effect of age on clearance to different values showed that the decrease in clearance per year of age was at least 0.

Table 4. Figure 2. The quality of fit of the pharmacokinetic model to the values for plasma concentration of rapacuronium. The x axis shows time in minutes after administration of rapacuronium.

The y axis shows the ratio of the measured concentration of rapacuronium to the value predicted by the population pharmacokinetic model left or the post hoc fit right. Each line represents a value from a single person. If the model fit the data perfectly, all lines would lie horizontally at 1.

The improved quality of fit of the post hoc values compared with those from the population model is expected in that the post hoc model permits interindividual variability, but the population model does not. In one volunteer, the initial aliquots of urine h were discarded accidentally. In the remaining healthy volunteers, urinary recovery of rapacuronium ranged from 5.

The plasma concentrations of ORG peaked immediately after administration in healthy volunteers, decreased rapidly, peaked again at approximately min, and decreased monotonically during the rest of the 8-h sampling period Figure 3.

For ORG, a two-compartment model was preferred to a one-compartment model; there was no additional improvement with a three-compartment model Table 5 , models The constant coefficient of error model yielded fits comparable to the error model with two components model 15 vs.

Permitting clearance and interindividual variability in clearance to differ between groups improved the quality of the fit model 18 vs. Additional models in which Cl distribution had both a constant and weight-normalized component model 20 , Cl distribution varied with age model 21 , or Cl renal varied with gender model 22 did not improve further the quality of the fit. A model in which interindividual variability was not permitted for V 1 model 23 yielded the same fit as model Permitting an administered dose of ORG did not improve the quality of the fit of the model model 24 vs.

Thus the optimal model Table 6 , Figure 4 for ORG had two compartments, and all pharmacokinetic parameters were weight normalized. In the nine volunteers with complete urine collections, urinary recovery of ORG ranged from 3.

Effect of Liver Disease on Pharmacokinetics

Pharmacokinetics is a term that describes the time course and fate of a drug in the body. The term encompasses drug absorption, distribution, metabolism, and elimination and is often referred to as drug disposition. Elimination is the removal of the drug from the body through different routes, including in urine, feces, and bile. Critically ill patients pose several challenges to health care providers that are related to medication pharmacokinetics. Organ dysfunction affects the safety and effectiveness of medications because many Sign In or Create an Account.


Renal failure may influence hepatic drug metabolism either by inducing or inhibiting hepatic enzymes, or by its effects on other variables such as protein binding, hepatic blood flow and accumulation of metabolites. This review examines all of these effects.


Metrics details. Infection and sepsis are a main cause of acute-on-chronic liver failure ACLF. Adequate dosing of antimicrobial therapy is of central importance to improve outcome. Liver failure may alter antibiotic drug concentrations via changes of drug distribution and elimination. In this prospective cohort study, patients received meropenem 1 g tid short-term infusion SI.

Liver and kidney function disturbances influence the pharmacodynamic and pharmacokinetic behaviour of drugs. Because of the differences in metabolism and excretion between the various muscle relaxants, liver and kidney disturbances do influence their pharmacodynamics and pharmacokinetics to a different extent. A description of the changes is given for the most frequently used non-depolarizing muscle relaxants.

Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: Susla and J. Susla , J.

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If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus. Please consult the latest official manual style if you have any questions regarding the format accuracy. Compare the advantages and disadvantages of the use of drugs or endogenous substances as markers for the measurement of renal function. Describe the relationships between creatinine clearance, serum creatinine concentration, and glomerular filtration rate. Describe quantitatively using equations how renal or hepatic disease can alter the disposition of a drug. Distinguish between hemodialysis and peritoneal dialysis and calculate dose adjustments of a drug in patients undergoing dialysis.


The pharmacokinetics of recombinant human granulocyte colony-stim ulating factor (rhG-CSF) was studied in rats experiencing renal and hepatic failure.


Background

Wright Assistant Professor of Anesthesia. Szenohradszky Assistant Professor of Anesthesia. Because renal function affects the elimination of muscle relaxants, each new muscle relaxant must be evaluated in patients with renal failure. Accordingly, the neuromuscular effects and pharmacokinetics of rapacuronium were identified in patients with renal failure. Rapacuronium 1.

Physiologically based pharmacokinetic PBPK modeling permits clinical scientists to reduce practical constraints for clinical trials on patients with special diseases. Also, the effect of age on pharmacokinetic parameters of both drugs was investigated in healthy population and in patients with renal and hepatic impairment. A full PBPK model was built in the simulator for clozapine and sildenafil based on physicochemical properties and observed clinical results. The PBPK model adequately predicted the pharmacokinetic parameters of clozapine and sildenafil for the healthy adult population. In the simulation results, the bioavailability of both drugs was remarkably raised in both renal and hepatic impairment in young and elderly populations. PBPK modeling could be helpful in the investigation and comparison of the pharmacokinetics in populations with specific disease conditions.

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Даже директор не ставил под сомнение чутье Мидж Милкен - у нее была странная особенность всегда оказываться правой.

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