Volume Of Distribution In Central Compartment Research Articles

Influence of a bacterial lipopolysaccharide on the pharmacokinetics of tobramycin in rats.

The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg-1) and inulin (100 mg kg-1) were administered intravenously 2 h after administration of 50, 250 or 500 micrograms kg-1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 micrograms kg-1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.

Influence of infused catecholamines on the pharmacokinetics of cocaine and benzoylecgonine formation after bolus dose or continuous cocaine administration in the rat.

The purpose of this study was to determine whether a catecholamine infusion administered to simulate a stress state could alter the pharmacokinetics of administered cocaine and effect the formation of benzoylecgonine, its major metabolite, in the rat. In a previous investigation we determined that catecholamine infusion enhanced the toxicity of continuous cocaine infusion by reducing the time before the onset of convulsions and respiratory arrest. We postulated that this enhanced toxicity was an effect of catecholamines on the pharmacokinetics of cocaine. To test this hypothesis we studied plasma cocaine and benzoylecgonine disposition after intravenous bolus administration of cocaine (5 mg kg(-1)) to 19 male Sprague-Dawley rats and to 10 rats which received an initial loading-dose cocaine infusion of 1 mg kg(-1) min(-1) (for 5 min) followed by continuous infusion of 100 microg kg(-1) min(-1). Rats in both studies randomly received either continuous catecholamine infusion comprising adrenaline (7.25 microg mL(-1)), noradrenaline (4.4 microg mL(-1)) and dopamine (8.0 microg mL(-1)) or saline, administered at a similar rate. Bolus dose cocaine administration, simultaneously with catecholamine infusion, resulted in significantly higher Cmax levels for cocaine (3.8 compared with 2.5 microg mL(-1)) and lower distribution half-lives (3.3 compared with 5.9 min) and central compartment volumes of distribution (1.5 compared with 2.1 L kg(-1)) compared with saline infusion. Benzoylecgonine formation was significantly reduced in rats receiving catecholamines whereas the elimination half-lives (26.3 compared with 25.0 min) and systemic clearances (146 compared with 146 mL kg(-1) min(-1)) were not different. Continuous cocaine infusion (after an initial loading infusion) resulted in the doubling of plasma cocaine levels in rats receiving catecholamines compared with the control group. These data indicate that elevated plasma catecholamines have significant effects on cocaine pharmacokinetics. This might serve to explain the enhanced toxicity from concomitant cocaine and catecholamine infusion demonstrated in previous experiments.

Population pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in chicken based on retrospective data, incorporating first-pass metabolism

A population pharmacokinetic (PPK) model for enrofloxacin and its metabolite ciprofloxacin in chicken based on retrospective data was developed. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were determined in blood samples from chicken administered either enrofloxacin via oral and intravenous routes or ciprofloxacin via intravenous injection. The disposition of enrofloxacin and ciprofloxacin was described simultaneously by an integrated mathematic model. Two compartments were used to describe the enrofloxacin and ciprofloxacin disposition profiles. The formation of ciprofloxacin was through the central compartment of enrofloxacin. The integrated model was estimated with nonlinear mixed effects model (NONMEM). The total clearance of enrofloxacin (CLEN) and ciprofloxacin (CLCP) was 0.613 L/h and 1.15 L/h, respectively. Correlation between CLEN, the central compartment volume of distribution for enrofloxacin (V2) and CLCP was estimated. After intravenous administration of enrofloxacin, the transformation rate of enrofloxacin to ciprofloxacin was 0.429 L/h. The bioavailability factor after oral administration was 0.926, and 12.6% of enrofloxacin after oral administration was transformed to ciprofloxacin via first-pass effect. Pharmacodynamic (PD) evaluation was performed using area under concentration time curve of active moiety from 0 to 24 h and MIC collected from literature. This study is the first one to use PPK method to investigate parent drug and its metabolite disposition and PDs using an integrated model in veterinary medicine.

Higher Doses of Rituximab May Be Required for Patients with CLL as Compared to NHL Based On Population Pharmacokinetic (PK) Modeling.

Abstract 1742Poster Board I-768 IntroductionIn the randomized Phase III study REACH, the combination of rituximab (R) (375 mg/m2 cycle 1, 500 mg/m2 cycles 2-6) and fludarabine (F) (25mg/m2 X 6 cycles) and cyclophosphamide (C) (250 mg/m2 X6 cycles) was shown to improve clinical response and prolong PFS in patients with relapsed/refractory Chronic Lymphocytic Leukemia (CLL) compared with F and C alone. The use of 500 mg/m2 as the dose of R in R-FC was guided by previous published data in CLL patients treated with R monotherapy demonstrating a probable dose-response relationship of a higher response rate at the higher dose levels (O'Brien JCO 2001, Byrd JCO 2001) and also by the data of high number of circulating malignant cells in CLL population (characteristic of CLL) which indicated that R might exhibit a higher clearance rate in CLL compared to observed clearance rates in NHL. Prior to the REACH study, the pharmacokinetics (PK) of R have not been thoroughly studied in the CLL population. As sub-study in REACH trial, a complete PK analysis of R was performed in CLL patients using a population PK analysis. This approach allowed not only the characterization of R PK in CLL patients, but also allowed for an opportunity to perform comparison of the PK differences between indications (CLL and NHL) and provided data-driven validation for the need of high R in CLL patients. Patients and MethodsThe PK of R were described with plasma concentrations from 21 CLL patients who received R-FC, using nonlinear mixed-effects modeling (NONMEM VI) software. A two-compartment model with time-varying clearance was validated using a bootstrap and visual predictive check method. The concentration vs. time profiles after given different dosages of R in NHL and CLL patients were predicted using the final models based on the observed data. ResultsR concentration data in CLL patients were well described by a two-compartment model with time-varying clearance, which has been used to describe R concentration data in NHL. Total clearance is comprised of two terms, a non-specific clearance pathway (CL1), which remains unchanged throughout treatment, and a specific clearance pathway (CL2) that decreases following a first-order decay rate from its initial value following the first infusion. The term Kdes represents the actual rate of change from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1). The typical population estimates of R nonspecific clearance (CL1), and central compartment volume of distribution (V1) are similar between CLL and NHL (171 vs. 138 mL/day; 2310 vs. 2710 mL, respectively).However, the specific clearance (CL2) in CLL was much faster than that in NHL (1280 vs. 577 mL/day), and the rate of change (Kdes) from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1) is two times lower for CLL patients compared to NHL patients (0.024 vs. 0.046 /day) and this suggests that it takes longer time for receptor saturation for CLL patients compared to NHL patients. The results of the simulation exercise showed that in the early cycles of the R-FC regimen, trough concentrations (Ctrough) and drug exposure (AUC) in CLL patients given 500 mg/m2 would be lower than those for NHL patients given 375 mg/m2 dose regimen. By the final cycles, the Ctrough and AUC of R are similar in NHL given 375 mg/m2 and CLL given 500 mg/m2. ConclusionsRetrospective population PK analysis of R in CLL patients using non linear mixed effect modeling confirmed an increased R clearance during the early cycle of treatment as compared to NHL patients. This increased clearance is potentially due to a higher number of malignant cells in circulation for CLL patients, thus a larger dominance of the faster receptor-mediated clearance component in these patients, which overcome the lower CD20 density in CLL. The dose regimen of 500mg/m2 in CLL patients allows for reaching steady state AUC which is similar to the steady state AUC achieved with doses of 375mg/m2 given in NHL patients. DisclosuresLi:Genentech: Employment. Zhi:Hoffmann-La Roche Inc.: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment. Valente:Genentech: Employment, Equity Ownership. Visich:Genentech: Employment.

Population Pharmacokinetics of High-Dose Methotrexate After Intravenous Administration in Pediatric Patients With Osteosarcoma

The goal of this study was to establish the population pharmacokinetics (PK) of high-dose methotrexate (HD-MTX) treatment in children with osteosarcoma and to explore the influence of patient covariates and between-occasion variability on drug disposition. Patient covariates and concentration-time data were collected. PK data analysis from 209 HD-MTX cycles from 14 patients was performed using the population approach (NONMEM V). Internal and external validations were performed to confirm the model. PK of methotrexate was best described by a 2-compartment open PK model with first-order elimination from the central compartment. Between-subject variability (BSV) was included in total plasma clearance (CL) and in central compartment distribution volume (V1) [coefficient of variation (CV) 11.9% and 8.9%, respectively]. The CV of BSV in the residual error was 25.5%. Between-occasion variability was only retained for CL (CV 8.2%). RE consisted of a proportional error of 41.6%. Age and body weight in CL and body weight in V1 were identified as the appropriate covariates. The final estimates of total CL and V1 were given by the equations CL = 88.5.(AGE/15) + 27.4 x (WGT/50) L/d and V1 = 11.0 + 5.6 x (WGT/50) L, respectively. Internal validation results showed that the 95% confidence interval covered all the observed MTX concentrations. Mean bias and precision of the individual predicted concentrations, calculated in a validation dataset, resulted in -1.36% and 19.71%, respectively. A population PK model was developed for HD-MTX in children with osteosarcoma. Validation studies confirmed the suitability of the model for further dose individualization by means of a Bayesian approach.

Clinical pharmacokinetics of bevacizumab in patients with solid tumors

To characterize the population pharmacokinetics of bevacizumab and the influence of demographic factors, disease severity, and concomitantly used chemotherapy agents on it's pharmacokinetic behavior. Data from eight clinical trials with bevacizumab administered by intravenous infusion were included. A total of 4,629 bevacizumab concentrations from 491 patients with solid tumors, who received bevacizumab doses ranging from 1 to 20 mg/kg at a dosing frequency ranging from weekly to every 3 weeks, were analyzed using a nonlinear mixed-effects modeling approach (NONMEM). The best structural model was a two-compartment model with first-order elimination. In the final model, estimated clearance (CL) and central compartment volume of distribution (Vc) were 0.207 L/day and 2.39 L for a typical female. The terminal half-life estimate was approximately 20 days for both men and women. Body weight and gender were the most significant covariates to explain interpatient variability for CL and Vc. Clearance was 26% faster in men than in women. Patients with low serum albumin and high serum alkaline phosphatase had 19 and 23% faster CL, respectively, than a typical patient. Consistent with the long elimination half life, simulations showed that similar steady-state exposures can be maintained when the weekly mg/kg dose rate is maintained, therefore allowing administration of bevacizumab to coincide with the frequency of administration of the cytotoxic agents. The PK parameters were consistent with those of other IgG molecules. The results support dosing bevacizumab on a once every 2 weeks or once every 3 weeks dosing schedule on a mg/kg basis.

Rituximab Exhibits a Long Half-Life Based on a Population Pharmacokinetic Analysis in Non-Hodgkin's Lymphoma (NHL) Patients.

The mean serum half life of rituximab reported in the current approved package insert (February 2007) is 76.3 and 205.8 hours following the first and fourth infusions, respectively. This results is based on data from 14 Non-Hodgkin's Lymphoma (NHL) patients treated with a dose of 375 mg/m2 weekly × 4 analyzed using non-compartmental analysis (NCA). The aims of the current analysis were:1.to develop a population pharmacokinetic (POP PK) model using a large NHL patient population2.to investigate possible mechanisms that may explain the observed increase in half-life with time such as a B-cell/tumor burden mediated clearance3.to identify covariates as potential predictors of PK variability.The population PK analysis was performed using NONMEM V based on 3739 rituximab serum concentration samples from 298 patients who received rituximab as a single agent or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy from six clinical studies. Tested covariates evaluated included body surface area (BSA), gender, age, race, WHO status, baseline CD19+ counts, sum of the tumor perpendicular diameters (SPD) of tumor and CHOP therapy. A non-parametric bootstrap procedure was used to estimate the precision of model parameters, and the model performance was assessed using visual predictive check. Rituximab concentration data were best described by a two-compartment model with time-varying clearance. Total clearance comprised of two terms, a non-specific clearance pathway (CL1), which remains unchanged throughout treatment, and a specific clearance pathway (CL2, B cells/tumor burden mediated), which decreased at a first-order decay rate from its initial value following the first infusion. The typical population estimates of rituximab nonspecific clearance (CL1), specific clearance (CL2), and central compartment volume of distribution (V1) were 0.14 L/day, 0.59 L/day, and 2.7 L, respectively. Age, gender, race, and WHO performance status had no effect on the PK of rituximab. Covariate analysis revealed that patients with higher CD19 counts or SPD of tumor burden at baseline had a higher rituximab CL2, while V1 varied by body surface area (BSA) and CHOP chemotherapy. However, unexplained inter-individual variability remained high for CL2 following correction for CD19/SPD. Changes from typical V1 values contributed by extreme BSA (1.53 to 2.32 m2) and concurrent CHOP therapy, were relatively minor (27.1% and 19.0%) and explained 27.3% and 5.75% of the inter-individual variability in V1, respectively. Dose adjustment for the tested covariates is not expected to result in a meaningful reduction in rituximab PK variability. Retrospective analysis of rituximab PK using non linear mixed effect modeling confirmed that rituximab elimination decreased following multiple infusions. The median of individual estimates of rituximab terminal half-life was 22 days (range, 6.1 to 52 days), which is typical for immunoglobulin isotype IgG in human and is longer than that reported for humanized anti-CD20 clinical candidates, IMMU106 and of atumumab of 12.0 and 14.3 days, respectively.

Teicoplanin Population Pharmacokinetic Analysis in Hospitalized Patients

The goal of this study was to build a population pharmacokinetic (PK) model to characterize the population PK parameters in our hospitalized patients. Teicoplanin serum concentrations from clinical routine were used. Antibiotic dose history and blood collection times were recorded and analyzed with NONMEM-V. Demographic and biologic data creatinine clearance (CLcr), weight (WT), and albumin (Alb) were tested for inclusion as covariates in the basic model. Intraindividual and residual variability were modeled. One hundred seven sparse samples (mainly trough levels), from 79 patients, were included. A 2-compartment PK model characterized by clearance (CL), central compartment volume of distribution (Vc), intercompartment clearance, and steady-state volume of distribution (VSS) with first-order elimination adequately described the data. CLcr and WT significantly influenced teicoplanin CL (CL = 0.57[0.15]*(1+0.0048[0.39]*(CLcr - averageCLcr)*WT) L/h). VSS was not affected by any covariate (VSS = 50.2[0.13]L). A negative trend between Alb and individual VSS estimates was observed without statistical significance. In a new data set, bias and precision resulted in mean values of -3.24% and 9.42%, respectively. In conclusion, CLcr and WT are significant covariates on teicoplanin CL. Results from predictive accuracy and precision show the usefulness of this model for implementation in a therapeutic drug monitoring program in the near future.

Time-dependent pharmacokinetics of cyclosporine (NeoralR) in de novo renal transplant patients

A model for the large scale temporal trend in the oral bioavailability of microemulsion cyclosporine (Neoral) (CsA) is established, with dependence on post-(renal) transplantation day (PTD). Twenty de novo adult renal transplant recipients were monitored for CsA administered orally q12 h. A model development group (11 patients, 315 blood concentration samples) was screened at 2 h (C(2); n = 92), 3 h (C(3); n = 56) and at predose troughs (C(min); n = 167) over periods of up to 75 days. The final model was tested in nine patients with C(min) (n = 580) monitored across 4-5 years. The doses varied between 100 and 538 mg with an apparent hyperbolic trend in C(2)/dose vs. PTD. A nonlinear mixed effects modelling (NONMEM) approach was used to obtain population and individual patient one-compartment pharmacokinetic (PK) parameters for oral CsA, which carry implicit the bioavailability (F). In the final PK model (PK-f) the F was modelled via a simple function for the temporal (days) trend of the bioavailability after transplantation as, F(f) = 1-alpha * exp(-lambda * PTD) resulting in a 28% reduction in the unexplained intra-individual variability. The population PK-f parameters were, for apparent clearance [mean, 95% confidence interval (interindividual CV%)] Cl/F(f) = 17.0 (13.8-20.2) L/h (27%), apparent central compartment volume of distribution, V/F(f) = 134 L (108-160) (28%), and lambda = 0.037/day (0.005-0.069) (120%). The absorption rate k(a) and the parameter alpha were approximated iteratively as 4/h and 0.62 respectively. The PK-f was structurally superior to the base model in explaining part of the within subject (occasion) variability and predicting the exposure surrogates C(2) and C(3). Also, the PK-f was better than the base model with Bayesian fitting of individual profiles in that group. The PTD-dependent relative bioavailability model provides a rational means of steering dose titration of CsA in de novo renal transplantation patients by removing the large scale PK adjustment signal, either through nomograms or as a Bayesian prior.

Can Bioimpedance Determine the Volume of Distribution of Antibiotics in Sepsis?

The relationship between the volume of distribution, assessed according to the two-compartmental pharmacokinetic model, and extracellular water estimated by bioimpedance was studied in mechanically ventilated patients with sepsis and capillary leak. A prospective observational study was performed in a twenty-bed general intensive care unit in the university hospital. Patients received either vancomycin (n = 16) or netilmicin (n = 12) for more than 48 hours. Those with ascites, pleural effusion, on renal replacement therapy or with haemodynamic instability were excluded. Serum concentrations of drugs were taken for pharmacokinetic analysis before, 1 hour and 4 hours after the 30 minute infusion. Bioimpedance measurement was performed at the time of the third sampling. The protocol was repeated after 24 hours. Fluid balance during the 24 hour interval was recorded. Extracellular water was increased and represented 45.6 to 46.6% of total body water Fluid balance correlated with the change of extracellular water (r = 0.82, P < 0.0001) and total body water (r = 0.74, P < 0.0001). Volumes of distribution of vancomycin (0.677 +/- 0.339 l/kg) and netilmicin (0.505 +/- 0.172 l/kg) were increased compared to normal values. A correlation was demonstrated between volume of distribution (Vd(area)) of vancomycin and extra cellular water/total body ratio (r = 0.70, P < 0.0001). The central compartment distribution volume (V1) of netilmicin correlated with extracellular water/total body water ratio (r = 0.60, P < 0.003). Serum concentrations above the recommended therapeutic range were detected in 81.2% of patients on vancomycin and in 50% of patients on netilmicin. Increased volumes of distribution can be estimated by the bioimpedance measurements but are not associated with requirements for higher dosage of the glycopeptide or aminoglycoside antibiotics.

Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass

Background Despite long use of protamine in cardiac operations, neither protamine concentrations nor pharmacokinetics have been reported in patients. Methods Twenty-eight patients (age, 26 to 80 years) undergoing various cardiac surgical procedures gave their consent to receive 250 mg of protamine sulfate administered intravenously by an infusion pump during 5 minutes. Protamine was administered at the usual intraoperative time after separation from cardiopulmonary bypass for reversal of heparin. Timed arterial blood samples were obtained after protamine infusion. Blood plasma was subjected to solid-phase extraction and high-performance liquid chromatography. Total (free + heparin-bound) protamine concentration versus time data were subjected to pharmacokinetic modeling. Results Twenty-six patients completed the study. Total plasma protamine concentrations declined rapidly. Model-independent pharmacokinetic analysis revealed median (range) values as follows: volume of distribution, 5.4 L (0.82 to 34 L); clearance, 1.4 L/min (0.61 to 3.8 L/min); and half-life, 4.5 min (1.9 to 18 min). Schwarz-Bayesian criterion identified a two-compartment exponential model with adjustment for weight in the central compartment volume of distribution as performing better than other compartmental or Michaelis-Menten models. Conclusions Protamine has a very short (approximately 5 minutes) half-life after a single 250-mg dose in adult patients. This short half-life could underlie recurrent anticoagulation after initial apparent reversal of heparin.

Pharmacokinetic analysis of dodecanedioic acid in humans from bolus data.

Excretion and tissue uptake of dodecanedioic acid (C12), a proposed alternative fuel substrate, was investigated in humans by bolus experiments. Seven overnight-fasting healthy male volunteers received i.v. a bolus (1 g) of C12. Blood samples were collected after C12 administration at intervals of 15 minutes, and C12 serum concentration was measured by high-performance liquid chromatography. C12 excretion in 24-hour urine was measured. Binding of C12 in human serum was determined in separate equilibrium dialysis experiments by means of an isotopic compound (disodic salt of (1,12)14C-dodecanedioic acid). A two-compartment model was used for describing C12 kinetics. The excreted amount of C12 in 24-hour urine was found to be, on the average, 1.62% of administered dose. The apparent number of binding sites per albumin molecule was 3.1 +/- 0.2 (estimate +/- SE) with an affinity constant of 6.4 +/- 1.8 mM-1. The distribution volume of central compartment was 5.56 +/- 3.13 L and that of peripheral compartment was 87.4 +/- 30.4 L. The rate constant of exchange between compartments was 4.60 +/- 3.50 L/min, that or urinary excretion 25.6 +2- 15.5 mL/min, and that of tissue uptake 2.17 +/- 0.86 L/min. These results are promising for C12 utilization in parenteral nutrition, because C12 elimination in urine is low whereas tissue uptake appears to be rather efficient.

Effect of intravenous L-carnitine on carnitine homeostasis and fuel metabolism during exercise in humans

This study was undertaken to challenge the hypothesis that short-term administration of carnitine during exercise can modify skeletal muscle carnitine homeostasis and fuel metabolism in normal humans. With a randomized, blinded, crossover design, subjects received carnitine or placebo at the start of a bicycle ergometer exercise session. During the 2 hours after intravenous administration of 185 mumol/kg carnitine, carnitine kinetics could be described with a central compartment volume of distribution of 200 ml/kg, a total clearance from this compartment of 1.9 ml/min/kg, and a renal clearance of 1.3 ml/min/kg. Carnitine administration had no effect on muscle total carnitine content or the workload-dependent accumulation of acylcarnitines in skeletal muscle. Carnitine had no effect on the respiratory exchange ratio, muscle lactate accumulation, plasma lactate concentration, muscle glycogen utilization, or plasma beta-hydroxybutyrate concentration during exercise. Thus the skeletal muscle carnitine pool is segregated from dramatic changes in the plasma carnitine pool, and short-term administration of carnitine has no significant effect on fuel metabolism during exercise in humans.

Pharmacokinetics of Recombinant Human Superoxide Dismutase

Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 +/- 1.7 min (mean +/- SEM), and the elimination half-life was 51.1 +/- 5.9 min; the central compartment volume of distribution (Vc) was 81 +/- 26 ml/kg and the steady-state volume of distribution was 156 +/- 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (micrograms/ml) for the dosage regimens were (a) 65 +/- 28, (b) 89 +/- 19, (c) 214 +/- 61, (d) 20 +/- 5, and (e) 86 +/- 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were less than 1% of serum levels, suggesting negligible rhSOD penetration into the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging and alfentanil disposition in healthy volunteers and surgical patients

We studied the pharmacokinetic disposition of alfentanil in 20 volunteers and in 15 surgical patients 20-72 years old. Pharmacokinetic disposition was first order and was well described by a two-compartment open model. Central-compartment volume of distribution was 0.131 +/- 0.087 L.kg-1 (mean +/- SD) in young healthy volunteers and decreased modestly with increasing age (r = -0.32, P less than 0.05). However, apparent volume of distribution at steady-state, 0.404 +/- 0.205 L.kg-1 for the whole study cohort, was not age-related. Plasma clearance of alfentanil in young healthy subjects, 9.3 +/- 6.3 ml.kg-1.min-1, also showed an inverse relationship with age (r = -0.54, P less than 0.001), and was not affected by surgical stress in subjects older than 60 years. Cigarette smoking and sex of the subjects did not contribute to interindividual differences in the kinetic disposition of this drug. Our finding that interindividual differences in disposition of alfentanil were the least in older subjects suggests that its pharmacological effects related to pharmacokinetic disposition should be most predictable in the elderly.

Pharmacokinetic differences between peripheral and central drug administration during cardiopulmonary resuscitation

Advanced resuscitation techniques are dependent on drug therapy to increase survival. Because drugs must reach their site of action instantaneously, the choice of appropriate route of administration may be critical. To study the pharmacokinetics of drug administration by peripheral and central venous routes during resuscitation, nine mongrel dogs were studied. Arterial blood pressure and electrocardiograms were monitored continuously. Cardiac output was evaluated before resuscitation to determine control levels. After thoracotomy and fibrillation of the heart, cardiac massage was started with a frequency of compression maintained at 60/min. Bolus injections of two different radioisotopes were given simultaneously through a peripheral and a central vein. Isotope activity was sampled through a catheter in the right femoral artery at 5 second intervals for 90 seconds and at 30 second intervals for 210 seconds. The major differences between the two routes of administration were that central injection produced a 270% higher peak concentration (p less than 0.001) and significantly shorter lag times to the first appearance of tracer (16 +/- 7 versus 38 +/- 13 seconds, p less than 0.05) and times to peak concentration (13 +/- 5 versus 27 +/- 12 seconds, p less than 0.01). In contrast, there were no significant differences in area under the time-counts curve, mean residence time, total body clearance and steady state volume of distribution. The central compartment volume of distribution was significantly smaller after central than after peripheral injection (26.1 +/- 56 versus 76.3 +/- 16.5 ml, p less than 0.01). The therapeutic implications of these findings must be investigated for individual drugs used during cardiorespiratory resuscitation to determine the most appropriate route and dosage for each agent.

Multiple-dose pharmacokinetics of imipenem-cilastatin.

We characterized the pharmacokinetic profile of imipenem-cilastatin administered intravenously to six normal volunteers in a dose of 1,000 mg of each drug every 6 h for 40 doses. The plasma concentrations of imipenem and cilastatin 1 h after the end of a 30-min infusion were 18.7 (+/- 2.1) and 19.1 (+/- 4.6), 20.0 (+/- 3.2) and 17.8 (+/- 4.8), and 23.4 (+/- 2.3) and 19.1 (+/- 3.5) micrograms/ml in the 1st, 17th, and 37th dosing intervals, respectively. The central compartment volumes of distribution for imipenem and cilastatin were 0.16 (+/- 0.05) and 0.14 (+/- 0.03) liter/kg, respectively. Elimination half-lives were short: 0.93 (+/- 0.09) h for imipenem and 0.84 (+/- 0.11) h for cilastatin. Plasma clearances were 12.1 (+/- 0.06) liters/h per 1.73 m2 for imipenem and 12.4 (+/- 1.1) liters/h per 1.73 m2 for cilastatin. Renal clearance accounted for 54% of the plasma clearance of imipenem and 69% of the plasma clearance of cilastatin. The concentrations of imipenem in plasma and urine remained above the MICs of the vast majority of pathogens throughout the dosing interval.

Methanesulfonic acid derivative of p,p'-diaminodiphenylsulfone. II. Pharmacokinetics and availability of parental drug in rabbit.

Pharmacokinetic studies on various methanesulfonic acid derivatives of p, p'-diamino-diphenylsulfone (Da) were carried out on rabbit and the liberation of parental Da was pursued. The general formula of the studied derivatives is NaO3SHC__RHN-C6H4-SO2-C6H4-NHC__RHSO3Na, where R are H-, CH3-, HOCH2 (CHOH)4-(promin) and C6H5-. The time courses of the blood concentration for all the derivatives and parental Da administered intravenously were represented in biexponential equations. The elimination rates of the water-soluble derivatives were about 10-fold larger than that of parental Da. The distribution volume of central compartment for Da was larger than those of the derivatives. No detectable amount of Da was found in blood after the i. v. administrations of promin and the derivative of R=H. From the viewpoint of drug availability, the area under liberated Da vs. time curve was compared to that of intact Da and deconvolution calculation was also carried out.