The absence of effect of azathioprine on prednisolone pharmacokinetics following maintenance prednisone doses in kidney transplant patients

Kidney transplant patients receive chronic prednisone and azathioprine for immunosuppression. However, the effect of azathioprine on prednisolone pharmacokinetics has not been determined in this population. Total and unbound prednisolone concentrations were determined, using high performance liquid chromatography and equilibrium dialysis, in eight kidney transplant patients following their usual oral maintenance dose of prednisone alone and concomitantly with their usual dose of azathioprine. The results showed no significant differences between the two groups in estimates of prednisolone plasma protein binding parameters and peak time, peak concentration, mean input time, clearance/F, volume of distribution/F, or half-life (t 1/2), using total or unbound prednisolone concentrations. Thus, the concomitant administration of azathioprine does not appear to alter the bioavailability or elimination of prednisolone at these doses.     

Pharmacokinetics of alcuronium in children with acyanotic and cyanotic cardiac disease undergoing cardiopulmonary bypass surgery

The aim of this study was to determine the pharmacokinetic parameters for alcuronium in children with cyanotic or acyanotic congenital cardiac disease undergoing cardiopulmonary bypass surgery and to compare these parameters with previously reported values in children and adults with normal cardiac function. Seven children with acyanotic disease and seven with cyanotic disease were studied. Alcuronium (base) was administered in an initial dosage of 0.25 mg·kg^?1 with additional doses as needed to maintain paralysis. Using time averaged data, cyanotic children had lower mean clearance, elimination half-life and volume of distribution at steady state than the acyanotic children; none of these differences was, however, statistically significant. In this study, children with acyanotic and cyanotic cardiac disease undergoing bypass, had a diminished clearance (P < 0.05) and a smaller volume of distribution (P < 0.05) than normal children and a shorter elimination half-life (P < 0.05) than adults. Onset of cardiopulmonary bypass caused an immediate marked decrease in alcuronium plasma concentrations which remained low in the acyanotic children at the completion of bypass.     

Glucocorticoid pharmacokinetics and growth retardation in children with renal transplants

Long-term glucocorticoid treatment contributes to the growth retardation in children after renal transplantation. We investigated whether determination of prednisone (PN) and prednisolone (PL) in plasma and PN, PL, and 6--hydroxyprednisolone (OH-PL) in urine could help to predict growth. PN and PL pharmacokinetics were studied in 36 children, from 5 to 15 years of age, receiving daily (D) or alternate-day (AD) oral PN treatment. Statural growth velocity was evaluated over a 1-year period. We compared three groups of children according to the growth kinetics during the study year (catch-up, stable, or decline) for clinical and pharmacokinetic parameters. A multiple linear regression analysis was performed in order to determine pharmacokinetic parameters able to explain height 1 year after inclusion. Height at the beginning of the study, creatinine clearance, and type of D or AD treatment explained 94.2% of height variance 1 year after inclusion. Only PL clearance was associated with growth evolution, but introduction of PL clearance in the multivariate model did not improve the variance of height accounted for by the previous model. We, therefore, do not recommend using glucocorticoid pharmacokinetics to predict growth retardation in children with renal transplantation.     

The relationship between cyclosporine pharmacokinetic parameters and subsequent acute rejection in renal transplant recipients

The best approach to determining the optimal dose of cyclosporine in renal transplant recipients is unclear. In this prospective investigation, CsA pharmacokinetic studies were performed in 45 patients 1, 4, and 12 weeks after the initiation of CsA. Data from 104 studies were then combined to analyze the relationship between CsA kinetic parameters and posttransplant clinical events. Random trough levels, used in the day-to-day adjustment of CsA dose, were examined separately in 19 of the 45 study patients. All CsA levels were measured with high-performance liquid chromatography. Results showed: (1) trough CsA levels, obtained by random sampling, or from the kinetic studies, correlated poorly with dose; however, there was a good correlation between CsA dose and maximum concentration (Cmax, r = .39, P less than .001), area under the concentration-time curve (AUC, r = .45, P less than .001), and terminal elimination half-life (r = .43, P less than .001); (2) several pharmacokinetic parameters correlated with subsequent rejection episodes; patients with acute rejection within 2 or 4 weeks after study had 15-31% lower Cmax (P less than .05) and 13-19% lower AUC (P less than .05) compared to those who were rejection-free; and (3) levels of blood constituents known to bind CsA also correlated with rejection, and this correlation was independent of the impact of kinetic parameters on rejection. Altogether, these results suggested that a limited number of CsA pharmacokinetic studies may be more useful than multiple, random trough levels in monitoring CsA therapy.     

Propofol as an induction agent in children: pain on injection and pharmacokinetics

The efficacy of lignocaine (1%) mixed with propofol in reducing pain on injection with propofol was studied in 40 children undergoing elective surgery in a double-blind, randomized comparison with glucose (5%). The pharmacokinetics of propofol in a single dose of 2.5 mg/kg was also studied in eight children participating in the same study. Lignocaine (1 mg) significantly reduced pain on injection compared to the control group (P less than 0.001). The induction characteristics of propofol were not affected by the lignocaine, and no undesirable interaction was found between the two drugs. The first-stage elimination half-life (t1/2 beta) of propofol in children was shorter (mean 9.3 +/- 3.8 (s.d.) min) than the values found in adults. This pharmacokinetic alteration may have clinical significance following repeated administration or continuous infusion of propofol.     

Pharmacokinetics of multiple-dose cefoperazone in hemodialysis patients

We studied the pharmacokinetics of cefoperazone 2 g i.v. every 12 h for 7 days in 12 patients on hemodialysis with normal hepatic function. The half-life of indocyanine green was determined in each patient via ear oximetry. Serum levels of cefoperazone during dialysis were well described by a two-compartment multidose infusion model. From this model we determined the steady state volume of distribution (Vdss), elimination phase half-life during dialysis T1/2D) and off hemodialysis (T1/2), and the corresponding elimination rate constants (KeD and Ke). Multiple correlations between pharmacokinetic parameters, liver function, and physical characteristics of the patients were evaluated. The T1/2 of cefoperazone was 2.9 h off compared to 2.3 h during hemodialysis. The corresponding elimination rate constants were Ke = 0.45/h versus KeD = 0.80/h. Cefoperazone clearances were 78 ml/min off dialysis compared to 140 ml/min during hemodialysis. Vdss was 0.20 liters/kg. The indocyanine green half-life ranged from 1.8 to 4.6 min with a mean of 2.7 min. The ages of the patients correlated with the beta phase half-life (r = 0.68, p = 0.015). We found no significant correlations among the other parameters including hepatic enzymes and indocyanine green half-life. Thus, hemodialysis approximately doubles the elimination rate constant (clearance), but, assuming drug redistribution kinetics remain unchanged, only shortens half-life by about 20%. Scheduling of a 12-hour dosing regimen to coincide with the end of hemodialysis should obviate any need for alteration of dose. Cefoperazone is thus unique among cephalosporins, since the half-life does not change appreciably with end-stage renal disease or dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of diazepam on the pharmacokinetics of intravenous and epidural bupivacaine in the rhesus monkey

Pretreatment of patients with diazepam has been reported to reduce the plasma half-life of epidurally administered bupivacaine. The concentrations of bupivacaine used to estimate its plasma half-life may be influenced by input into the vascular system (rate and extent of absorption from the epidural space) and disposition (distribution and elimination). We conducted a study in Rhesus monkeys in which the input function was known and the influence of intravenous diazepam on the disposition of intravenous bupivacaine could be delineated. Results indicated no differences in the primary pharmacokinetic parameters (i.e., total clearance and volume of distribution) for the disposition of bupivacaine. To determine whether the apparent disparity between these results and a previous study might be due to a diazepam-induced alteration in the input function, the influence of intravenous diazepam or saline on the mean absorption time of epidurally administered bupivacaine was also studied in monkeys. Epidural bupivacaine was completely absorbed whether the animals received intravenous saline or intravenous diazepam. No significant differences in pharmacokinetic parameters were found between animals pretreated with intravenous saline or intravenous diazepam and receiving an epidural injection of bupivacaine. The mean residence time of bupivacaine in the body (P less than 0.01) and plasma elimination half-life (P less than 0.005) were significantly longer after epidural administration than after intravenous administration. Intravenous diazepam does not alter the pharmacokinetics of intravenously or epidurally administered bupivacaine.     

The long-term outlook to final outcome and steroid treatment results in children with idiopathic nephrotic syndrome

Abstract

Idiopathic Nephrotic Syndrome (INS) was defined as combination of a nephrotic syndrome and non-specific histological abnormalities of the kidney. Among these abnormalities, minimal change nephrotic syndrome (MCNS) is the most common. We report our experience with MCNS; its clinical course, treatments and outcomes. One-hundred twenty children (66 male, 54 female) with MCNS, admitted to Nephrology Department between 1987–2009 was assessed. Their clinical presentations, treatment and disease courses were reviewed. The mean duration of follow-up was 11.5?±?1.9 years. Initially, all patients given prednisone 2?mg/kg/ day single dose per four weeks a followed by eight weeks of the same daily dose given every other day. After week 12, prednisone was progressively tapered off at the rate of 0.5?mg/kg per 15 daily intervals until complete discontinuation had been achieved by week 16. Steroid resistance was accepted as no achievement of remission following four weeks of prednisone 2?mg/kg/day followed by three intravenous pulses of corticosteroids. At the end of the initial steroid treatment, 106 (88.3%) patients were determinate steroid responsive while 14 (11.7%) patients were steroid resistance. Thirty-eight patients underwent biopsy. At the end of study recovery rate was increased from 88.3% to 94.1%. In conclusion, most of patients entered remission by our therapy end of follow up time. With the support of our satisfactory results among the whole study group, long-term prednisolone treatment still remains valid.     

Evidence that cyclosporine does not affect the metabolism of prednisolone after renal transplantation

The following investigation was performed to establish whether renal transplant patients treated with cyclosporine and prednisone have a decreased prednisolone catabolism and/or an increased systemic availability of oral prednisone when compared with patients treated with azathioprine and prednisone. Therefore we assessed, by HPLC and equilibrium dialysis, the total concentrations of prednisolone and prednisone and the unbound concentrations of prednisolone in plasma samples collected over 24 hr, and the 24-hr urinary excretion of prednisolone, prednisone, and 6 beta-hydroxyprednisolone after an i.v. dose of prednisolone and an equal oral dose of prednisone in 25 renal transplant patients on cyclosporine and in 25 patients on azathioprine and prednisone one month after transplantation. The metabolic clearance, the renal clearance, the volume of distribution, and the systemic availability of total and unbound prednisolone were identical in patients with and without cyclosporine. The apparent activities of the oxidoreductases involved in the biotransformation of prednisone into prednisolone and vice-versa were not affected by cyclosporine therapy. The fractional urinary excretions of 6 beta-hydroxyprednisolone increased with increasing metabolic clearance rate of prednisolone (r = 0.50, P less than 0.001). This relationship was not modulated by cyclosporine, indicating that cyclosporine does not affect the activity of the microsomal P-450-dependent 6 beta-hydroxylase. Thus, early after transplantation, patients on cyclosporine have a normal metabolism of prednisolone.     

Bupivacaine pharmacokinetics during epidural anaesthesia in children

Blood concentrations and pharmacokinetic parameters of bupivacaine were measured after epidural injection in children aged from 1 to 7 years. The children were allocated to two groups. In Group 1 (five children), pharmacokinetic parameters were measured after a single bolus injection of bupivacaine 0.25% with adrenaline 1:200,000. In Group 2 (eight children), pharmacokinetic parameters were measured after the initial injection and the second injection. The same local anaesthetic was used. The volume of the second injection was half of the initial volume. In children of Group 1, maximum mean concentration (CPmax) was 0.64 +/- 0.05 microgram ml-1, time to maximum concentration (Tmax) 19.2 +/- 3.9 min, vascular absorption (T1/2 abs) 4.3 +/- 1.5 min, terminal half-life (T1/2 beta) 227 +/- 37.7 min, volume of distribution (Vd) 3.4 +/- 0.51 kg-1, and total body clearance (Clt) 11.0 +/- 2.0 ml min-1 kg-1. When compared to an adult's pharmacokinetic parameters, both Vd and Clt were increased, so that T1/2 beta remained essentially unchanged. In children of Group 2, the first repeat injection was performed at 110 +/- 6.9 min. Mean CPmax increased significantly (20% after the second injection), whereas the values of the pharmacokinetic parameters measured did not differ significantly from those measured in children in Group 1. The results obtained in the present study demonstrate that the pharmacokinetic parameters of bupivacaine in children do not differ markedly from those reported in adults and that in the recommended dosage, the mean maximum concentrations, even after the second injection, are less than the presumed toxic levels.     

Pharmacokinetics of ketamine in man.

A method for the analysis of ketamine and of its metabolites is described using gas-liquid chromatography for separation and flame ionization detection. The lower limit of detection for ketamine in serum was 0.025 mug/ml. The pharmacokinetic behaviour of ketamine after intravenous injection may be described in terms of an open two-compartment model. The serum half-life of ketamine was in alpha-phase about 11 min, the predominant half-life for the beta-phase 2.5 h. The half-life of ketamine and its metabolities in urine was comparable to that in serum. It could be shown that the duration of anaesthesia is not only correlated ti ist rapid metabolic breakdown and elimination, but also to the distribution of the drug peripheral tissue.     

Long versus standard initial steroid therapy for children with the nephrotic syndromeA report from the Southwest Pediatric Nephrology Study Group

A retrospective cohort study was conducted by the Southwest Pediatric Nephrology Study Group (SPNSG) to address whether a longer initial course of corticosteroids in patients with idiopathic nephrotic syndrome (INS) provides superior protection against relapse without increased adverse effects. In order to be included in the evaluation, patients with INS must have responded to an initial steroid course, either standard or long regimen as defined here, and completed at least 1 year of follow-up. The standard regimen consisted of prednisone 2.0+/-0.3 mg/kg per day or 60+/-10 mg/m(2) per day for 28+/-4 days, followed by alternate-day prednisone for 4-12 weeks. The long regimen consisted of daily prednisone 2.0+/-0.3 mg/kg per day or 60+/-10 mg/m(2) per day for 42+/-6 days, followed by alternate-day prednisone for 6-14 weeks. The primary outcome measure was relapse of NS within 12 months of discontinuing the initial course of prednisone. There were 151 children who met the criteria for the study; 82 received the standard regimen and 69 the long regimen. The two groups did not differ in age, race, blood pressure, serum albumin, or serum cholesterol prior to the initial steroid course. The cumulative prednisone dose was 49% higher in the long regimen group than in the standard regimen group. Relapse within 12 months was reported in 72.5% of patients who received the long regimen versus 84.1% of those who received the standard regimen. The odds ratio for relapse within 12 months was 0.496 (95% confidence interval 0.22, 1.088), long versus standard regimen. This did not reach statistical significance ( chi(2)=3.058, P=0.08). The odds ratio of experiencing at least one side effect was 3.76, long relative to standard regimen ( n=133, P<0.001). Our data suggest that prolongation of the steroid treatment for the initial episode of steroid-sensitive NS may have a beneficial effect, but at the cost of increased side effects. However, definitive conclusions are limited by the retrospective design of the study and the number of patients. This may have caused failure to achieve statistical significance on the basis of a type II error.     

Prednisone metabolism in recipients of kidney or liver transplants and in lung recipients receiving ketoconazole

BACKGROUND: Actual prednisone exposure in low-dose prednisone regimens, in part determined by cytochrome P450 metabolism, has been shown to be important for allograft survival. METHODS: Prednisolone (the principal active metabolite of prednisone) metabolism was determined in eight nontransplant patients and in transplant recipients receiving oral prednisone maintenance therapy (20 kidney and 6 liver recipients receiving cyclosporine [CsA] and eight lung recipients receiving ketoconazole and CsA or tacrolimus [FK506]). RESULTS: Prednisolone area under the curve (AUC)-dose-normalized (PNAUCn) to 1 mg/kg was 8,288+/-1,513 ng.hr/mL in kidney recipients, versus 4,826+/-999 ng/mL per hr in healthy subjects (P<0.001); it was also increased in liver recipients versus healthy subjects (11,456+/-1,214 ng.hr/mL, P<0.001). Liver recipients also metabolized prednisolone more slowly than kidney recipients (P<0.001). PNAUCn in lung recipients was similar in kidney recipients despite the effect of ketoconazole to slow CsA metabolism. In kidney transplant recipients, the rate of CsA metabolism was correlated with the rate of prednisolone metabolism (r=0.54, P=.026). Basal cortisol levels in all transplant recipients were lower than in healthy subjects, suggesting more prednisolone exposure in transplant patients. CONCLUSIONS: Prednisolone metabolism is slower in solid-organ transplant recipients than in healthy subjects. The slower metabolism of prednisolone, particularly in liver recipients, may help explain the immunologic effectiveness of low-dose prednisone regimens in these patients.     

Longitudinal follow-up of bone mineral density in children with nephrotic syndrome and the role of calcium and vitamin D supplements.

BACKGROUND: We previously have demonstrated that children with idiopathic nephrotic syndrome (INS) are at risk of metabolic bone disease (MBD). In this study, we report the longitudinal follow-up of these children and the role of calcium and vitamin D supplements. METHODS: We prospectively studied 100 consecutive children with INS. They were treated with prednisone. All were subjected to a baseline clinical, biochemical and radiological evaluation. They were initiated on calcium (500 mg/day) and vitamin D3 (200 IU/day) supplements, followed by a repeat assessment. The primary outcome measure was the Deltaz score (difference between the initial and final z scores) on dual energy X-linked absorptiometry (DEXA). A univariate and multivariate analysis using stepwise linear regression was performed for factors predictive of an improved Deltaz score. RESULTS: Of the 88 children that completed the study, the majority (n = 54) had improved bone mineral density (BMD) at the spine, and another 25 children had stable BMD on calcium and vitamin D3 supplements. The mean spinal BMD values were significantly better on follow-up (0.607+/-0.013 g/cm2) as compared with baseline values (0.561+/-0.010 g/cm2) (P<0.0001). The interval between initial and follow-up assessment was 1.5+/-0.07 years. Children who were on these supplements (n = 73) had a significantly improved z score as compared with those who did not receive them (n = 15) (P = 0.008). On multivariate analysis, the factors predictive of an improved z score were: younger age (P<0.0001), calcium and vitamin D3 supplement (P<0.0001), greater dietary calcium intake (P = 0.022) and lower interval steroid dose (P = 0.001). CONCLUSIONS: Children with greater steroid doses were likely to have low BMD on follow-up. Calcium and vitamin D supplements may help in improving BMD in children with INS.     

Pharmacokinetics of oral tramadol drops for postoperative pain relief in children aged 4 to 7 years--a pilot study

Tramadol hydrochloride is an analgesic with mu receptor activity suitable for administration to children as oral drops. As the serum concentration profile and pharmacokinetic parameters in young children are not known via this route, we studied 24 healthy ASA 1 children to determine those parameters. The children's mean age was 5.3 +/- 1.1 years and their mean weight was 17.8 +/- 3.1 kg. They underwent general anesthesia with sevoflurane for dental surgery. The mean duration of anesthesia was 27.9 +/- 10.1 minutes. Tramadol 1.5 mg/kg (this dose was chosen because we have previously shown it to be effective in providing analgesia following pediatric dental surgery) was administered as oral drops 30 minutes before anesthesia. Venous blood samples were taken following the tramadol at 30-minute intervals for 4 hours, every 2 hours for 6 hours, and every 4 hours for 12 hours. The samples were centrifuged and the serum stored at -20 degrees C, and nonstereoselective gas chromatography was used to determine the concentration of (+) and (-) tramadol enantiomers plus their o-demethyltramadol (M1) metabolite concentrations. The tramadol absorption was rapid, the maximum measured serum concentration present occurring before the first sample at 30 minutes. That first sample had a concentration of 352 +/- 83.4 ng/mL. The concentration remained above the 100 ng/mL analgesic level until 6.8 +/- 0.9 hours. The elimination half-life was 3.6 +/- 1.1 hours, the serum clearance 5.6 +/- 2.7 mL/kg/min, and the volume of distribution 4.1 +/- 1.2 L/kg. The (+) enantiomer concentration was 14.2 +/- 4.9% greater than that of the (-) enantiomer. The M1 metabolites had a (-) enantiomer concentration 92.3 +/- 75.1% greater than the (+) enantiomer. From the peak concentration at 4.5 +/- 1.5 hours, the concentration of the metabolite was approximately one third that of the parent drug. The M1 elimination half-life was 5.8 +/- 1.7 hours. Apart from the rapid rise in the serum concentration, these kinetic parameters are similar to those seen in healthy young adults. The concentration profile supports an effective clinical duration in the region of 7 hours.     

Fracture Risk Associated with Different Types of Oral Corticosteroids and Effect of Termination of Corticosteroids on the Risk of Fractures

We conducted a case–control study on fracture risk associated with the use of orally administered prednisolone/prednisone, budesonide, methylprednisolone, and hydrocortisone to assess if the various preparations were associated with different fracture patterns. Cases were all subjects with any fracture sustained during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. Adjustments were made for concurrent diseases, use of other drugs, and a number of other factors. Oral prednisolone/prednisone was associated with a dose-dependent increase in fracture risk starting from a dose of around 6.7 mg/day. Oral budesonide was not associated with an increase in overall fracture risk, but the doses in general were low (<3 mg/day). Oral hydrocortisone was not associated with overall risk of fractures. Oral methylprednisolone was only used intermittently and was not associated with an increase in overall fracture risk at the low doses used. After termination of oral prednisolone/prednisone, it took more than 1 year for fracture risk to return to the levels of the background population. Oral prednisolone is associated with a dose-dependent increase in overall fracture risk. Budesonide at low doses did not seem to be associated with fracture risk. Hydrocortisone was not associated with an increase in the risk of fractures. It may take a year from last use of prednisolone/prednisone before fracture risk returns to that of the general population.     

Vancomycin Pharmacokinetics in Spinal Cord Injured Patients: A Comparison with Age-matched,Able-bodied Controls

Abstract

To compare the pharmacokinetics of vancomycin in chronic spinal cord injured patients and hospitalized, age-matched, able-bodied controls, we evaluated 14 spinal cord injured patients and 14 controls. Pharmacokinetic parameters of total body clearance (CL), distribution volume (V), elimination rate constant (k) and elimination half-life (ti/2) were calculated from two steady-state vancomycin serum concentrations by the method of Sawchuk and Zaske. Demographic data such as age, ideal body weight (IBW), total body weight (TBW) and serum creatinine at start of therapy (SCr), pharmacokinetic parameters and predicted dosages to achieve specific peak (30 mcg/ml) and trough concentrations (5–10 mcg/ml) were calculated for both groups. Statistical comparisons were made using a two sample, Student’s t-test. Demographic data between groups differed only in mean serum creatinine (p=0.04). There were no statistically significant differences in mean pharmacokinetic parameters of CL and V or mean predicted dosages. Mean elimination rate constant was significantly smaller and mean elimination half-life was significantly longer in spinal cord injured patients (p=0.02 and p=0.04, respectively). The longer dosing interval predicted in spinal cord injured patients trended toward statistical significance (p=0.10). We conclude that with chronic spinal cord injury, 1) the elimination half-life of vancomycin is increased and these patients may require longer dosing intervals and 2) distribution volume and predicted vancomycin doses are unaltered compared with controls. (J Spinal Cord Med;) 8:233–235)     

Stereoselective pharmacokinetics of ketorolac in children, adolescents and adults

BACKGROUND: Previous pharmacokinetic studies on racemic ketorolac using nonstereoselective analytical methods have indicated that the plasma clearance of ketorolac is higher and the volume of distribution greater in children than in adults. The aim of this study was to study the stereoselective pharmacokinetics of racemic ketorolac in children, adolescents and adults. METHODS: 18 children (6-11 yrs), 18 adolescents (12-17 yrs) and 18 adults (18-44 yrs) participated in the study. At the end of eye surgery they were given intravenous racemic ketorolac tromethamine 0.5 mg/kg. Plasma samples were assayed for (R)- and (S)-ketorolac with high-pressure liquid chromatography. Clearance (CL), volume of distribution at steady state (Vss) and elimination (Vz) and elimination half-life (t1/2,z) were calculated with standard methods. Incidence of side-effects were recorded. RESULTS: CL, Vss, Vz and t1/2,z were higher (P<0.05) for (S)-ketorolac than for the (R)-enantiomer. Vss of the active (S)-enantiomer was higher in children than in adolescents (P<0.05) and adults (P<0.001) but the values for CL were similar. Due to the higher volume of distribution, t1/2,z was also higher in children than in adults. The pharmacokinetics of the (R)-enantiomer were essentially unaffected by age. CONCLUSION: On a pharmacokinetic basis, the maintenance dose requirements of ketorolac are similar in children, adolescents and adults.     

Métabolisme et pharmacocinétique de l''atracurium

Atracurium is a new neuromuscular blocking agent which has an unique mode of elimination by spontaneous degradation in slightly alkali solution, according to the Hofmann elimination. The Hofmann elimination is completed in plasma (in vitro or in vivo) by an ester hydrolysis. The major degradation product is laudanosine. Metabolites can be considered as pharmacologically inactive with the usual doses of atracurium. Spontaneous degradation of atracurium in plasma is the major route of elimination in man and contributes to a short elimination half-life (approximatively 20 min). Distribution half-life is short and central and peripheral volumes are small when compared with the usual neuromuscular blocking agents. The pharmacokinetic parameters give a rapid dynamic equilibrium so that incremental doses will not lead to accumulation phenomenon. Because of spontaneous degradation of atracurium in plasma, its kinetics are theoretically independent of renal and liver functions. Only a slight increase of distribution volumes can be seen in very severe renal/hepatic failure. Atracurium pharmacokinetics could theoretically be modified by some modifications of acid-base equilibrium or alterations of thermoregulation. Pharmacokinetic studies are not yet available in these areas.