Volume Of Distribution Values Research Articles

P4-292: Regional variations in age dependence of P-gp–mediated transport across the blood-brain barrier measured using ( R)-[ 11C]verapamil and PET

(R)-[11C]verapamil is a positron emission tomography (PET) tracer for assessing the function of the blood-brain barrier efflux pump P-glycoprotein (P-gp). Previous studies have shown an increase in whole brain volume of distribution (VT) of (R)-[11C]verapamil with age, consistent with an age related decline in Pgp function. The aim of the present study was to assess regional variations in age dependency of P-gp function using regions of interest (ROI) and voxel based methods. (R)-[11C];verapamil scans were acquired in fifteen healthy male subjects over three age groups: young (aged 21–27; N=5), middle aged (aged 39–49; N=5) and elderly (aged 59–68, N=5). All subjects underwent a 60 min dynamic 3D PET scan after administration of 370 MBq (R)-[11C]verapamil. Arterial blood was sampled continuously and metabolites determined in order to generate a metabolite corrected input curve. PET images were co-registered with segmented T1-weighted MRI images and ROI were projected onto images using an automated MRI based template. VT values were determined using a single tissue compartment model after correction of plasma radioactivity for polar metabolites. Age dependency of VT was assessed both between age groups and using correlative analysis. Mean whole brain grey matter VT values for all subjects ranged from 0.51 to 0.83. A significant difference between young and both elderly groups, pooled or separately, was found in all cortical grey matter regions (p<0.005). No significant difference between the middle aged and elderly groups was found. A significant positive correlation between VT and age was found in thalamus and putamen (r2 0.61 and 0.59, respectively). There was a reduction in P-gp function with age in all brain regions studied, as indicated by a significant increase in VT of (R)-[11C]verapamil. The most prominent difference was observed in the thalamus.

Steady‐State Pharmacokinetics and Pharmacodynamics of Meropenem in Hospitalized Patients

To evaluate the steady-state pharmacokinetics and pharmacodynamics of meropenem 500 mg every 6, 8, and 12 hours, based on renal function, in hospitalized patients. Prospective, open-label, steady-state pharmacokinetic study. One tertiary care medical center and one community hospital. Twenty adult patients (12 men, 8 women) with suspected or documented bacterial infections requiring antimicrobial therapy. Patients received 30-minute infusions of meropenem 500 mg every 6 hours (group 1), every 8 hours (group 2), or every 12 hours (group 3) based on estimated creatinine clearances greater than 60, 40-60, or 10-39 ml/minute, respectively. Serial blood samples were collected after 2 or more days of therapy. Meropenem concentrations were determined by high-performance liquid chromatography, and pharmacokinetic data were analyzed by noncompartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for a percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC) of 40% by using pharmacokinetic data for each group and MIC data for seven gram-negative pathogens from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC, 2004-2005) database. Maximum and minimum serum concentrations (mean +/- SD) were 29.2+/-9.8 and 2.4+/-1.1 microg/ml, 33.2+/-8.5 and 3.8+/-2.7 microg/ml, and 33.5+/-4.7 and 4.9+/-1.6 microg/ml for groups 1, 2, and 3, respectively. The half-life values were 2.5+/-0.9, 3.4+/-1.3, and 6.1+/-1.4 hours, and the values for volume of distribution at steady state were 29.3+/-8.7, 23.8+/-8.1, and 28.7+/-8.6 L for groups 1, 2, and 3, respectively. For all three groups, the CFR was greater than 90% for the enteric pathogens and Pseudomonas aeruginosa and 82.4-85.2% for Acinetobacter species. Pharmacodynamic analyses suggest that regimens of meropenem 500 mg every 6, 8, or 12 hours, adjusted for renal function, are acceptable for treatment of infections caused by enteric gram-negative pathogens and P. aeruginosa. However, more aggressive dosing or alternative dosing strategies may be necessary for Acinetobacter species.

Partial volume corrected image derived input functions for dynamic PET brain studies: Methodology and validation for [11C]flumazenil

Extraction of arterial input functions from dynamic brain scans may obviate the need for arterial sampling and would increase the clinical applicability of quantitative PET studies. The aim of the present study was to evaluate applicability and accuracy of image derived input functions (IDIFs) following reconstruction based partial volume correction (PVC).Settings for the PVC ordered subset expectation maximization (PVC-OSEM) reconstruction algorithm were varied. In addition, different methods for defining arterial regions of interest (ROI) in order to extract IDIFs were evaluated. [11C]flumazenil data of 10 subjects were used in the present study. Results obtained with IDIFs were compared with those using standard on-line measured arterial input functions. These included areas under the curve (AUC) for peak (1–2 min) and tail (2–60 min), volume of distribution (VT) obtained using Logan analysis, and VT and K1 obtained with a basis function implementation of a single tissue compartment model.Best results were obtained with PVC-OSEM using 4 iterations and 16 subsets. Based on 11C point source measurements, a 4.5 mm FWHM (full width at half maximum) resolution kernel was used to correct for partial volume effects. A ROI consisting of the four hottest pixels per plane (over the carotid arteries) was the best method to extract IDIFs. Excellent peak AUC ratios (0.99±0.09) between IDIF and blood sampler input function (BSIF) were found. Furthermore, extracted IDIFs provided VT and K1 values that were very similar to those obtained using BSIFs.The proposed method appears to be suitable for analysing [11C]flumazenil data without the need for online arterial sampling.

Evaluation of the Metabotropic Glutamate Receptor Subtype 5 Using PET and 11C-ABP688: Assessment of Methods

(11)C-ABP688 is a new PET ligand to assess the subtype 5 metabotropic glutamate receptor (mGlu(5)). The purpose of this study was to evaluate different methods for the analysis of human (11)C-ABP688 data acquired from 6 healthy, young volunteers. The methods were a 1-tissue-compartment model (K(1), k(2)''), a 2-tissue-compartment model (K1-k4), and the noncompartmental method developed by Logan. Parameters related to receptor density were the total distribution volume (DV), DV'' (= K(1)/k(2)'', 1 tissue compartment); specific DV, DV(C2) (= K(1)/k(2)' x k(3)'/k(4), 2 tissue compartments); and DV(tot) for the noncompartmental method. The 1-tissue-compartment model was too simple to adequately fit the data. DV(C2) calculated with the 2-tissue-compartment model ranged from 5.45 +/- 1.47 (anterior cingulate) to 1.91 +/- 0.32 (cerebellum). The corresponding values for DV(tot), calculated with the 2-tissue-compartment model and the Logan method (in parentheses), were 6.57 +/- 1.45 (6.35 +/- 1.32) and 2.93 +/- 0.53 (2.48 +/- 0.40). There was no clear evidence of a region devoid of mGlu(5) receptors. The first-pass extraction fraction exceeded 95%. The minimal scan duration to obtain stable results was estimated to be 45 min. (11)C-ABP688 displays favorable kinetics for assessing mGlu(5) receptors. For tracer kinetic modeling, 2-tissue-compartment models are clearly superior to models with only 1 tissue compartment. In comparison to the compartmental models, the Logan method is equally useful if only DV(tot) values are required and fast pixelwise parametric maps are desired. The lack of regions devoid of receptors limits the use of reference region methods that do not require arterial blood sampling. Another advantage of the tracer is the fast kinetics that allow for relatively short acquisitions.

Kinetic evaluation in nonhuman primates of two new PET ligands for peripheral benzodiazepine receptors in brain

Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are, thereby, biomarkers of cellular inflammation in brain. We recently developed two PET ligands with an aryloxyanilide structure to image PBRs and now evaluate the kinetics of these radiotracers in monkey to determine whether they are suitable to explore in human. Baseline and receptor-blocking scans were performed with [(11)C]PBR01 and [(18)F]PBR06 in conjunction with serial measurements of the arterial plasma concentration of parent radiotracer separated from radiometabolite. We used brain and plasma data with compartmental modeling to calculate regional brain distribution volume, which is equal to the ratio at equilibrium of the concentration of radioligand in brain to that of plasma. The distribution volume of [(11)C]PBR01 was inaccurately estimated in the baseline scans, possibly because of the short half-life of (11)C or the presence of radiometabolite in brain. In contrast, the distribution volume of [(18)F]PBR06 was stably determined within 200 min of scanning, and nondisplaceable uptake was only approximately 10% of total brain uptake. [(18)F]PBR06 is promising for use in human because brain activity could be quantified with standard compartmental models and showed higher ratios ( approximately 10:1) of specific to nonspecific uptake. A critical factor for human use will be whether the tracer has adequately fast wash out from brain relative to the half-life of the radionuclide to obtain stable values of distribution volume.

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics. The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring. A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 +/- 0.2 l h(-1). Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 +/- 0.5 days, with a maximal value of 5.6 l h(-1). Moreover clearance increased by approximately 1.6 fold (range 0.5-1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 +/- 13 l kg(-1)) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F. The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

What is already known about this subject • In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra‐ and interpatient variability.• Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients. What this study adds • Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.• Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.Aims The use of tacrolimus is complicated by its narrow therapeutic index and wide intra‐ and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.Methods The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.Results A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h−1. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h−1. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was &gt;25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg−1) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.Conclusions The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.

Estimation of Volume of Distribution in Humans from High Throughput HPLC-Based Measurements of Human Serum Albumin Binding and Immobilized Artificial Membrane Partitioning

The volume of distribution (VD) in humans of 179 known drug molecules (acids, bases, and neutrals) has been modeled using two biomimetic-binding measurements. The phospholipid binding (log K (IAM)) and the plasma protein binding (log K (HSA)) have been calculated from gradient HPLC retention times on immobilized artificial membrane (IAM) and on human serum albumin (HSA) columns, respectively. The log VD values showed good correlation with the compounds' relative binding to IAM and HSA as follows: log VD=0.44 log K (IAM)-0.22 log K (HSA)-0.66; n=179, r2=0.76, s=0.33, and F=272. It was also observed that positively charged molecules bind relatively more to IAM, while negatively charged ones bind more to HSA, in line with the empirical observation that bases tend to have a larger volume of distribution than acids. These results suggest that with the help of these two simple high throughput HPLC-based biomimetic binding measurements an important in vivo drug disposition property can be estimated for use in early drug discovery.

Feasibility of central cannabinoid CB 1 receptor imaging with [ 124I]AM281 PET demonstrated in a schizophrenic patient

We studied central cannabinoid CB 1 receptors in a schizophrenic patient using the pyrazole derivative AM281 labelled with the positron-emitting nuclide iodine-124. A dynamic positron emission tomography (PET) acquisition with simultaneous blood sampling was performed up to 1.5 h post-injection. The classical Logan plot analysis was applied to generate a three-dimensional map of distribution volume (DV). The map was spatially normalised into the Montreal Neurological Institute stereotactic space. Using a volume of interest (VOI) template, mean values of DV were extracted from multiple grey matter regions and white matter (as a reference). As a measure of regional receptor availability, ratios of DV in grey matter to DV in white matter minus one (DVR − 1) were calculated. The highest receptor binding was observed in the striatum and the pallidum (DVR − 1: 0.35–0.37). Binding in basal ganglia regions was lower on the left than the right side. Moderately high binding was seen in the frontal cortex (0.22), the temporal cortex (0.18) and the cerebellum (0.15). In conclusion, 124I-AM281 PET can be used to reveal areas with prominent CB 1 receptor binding. Nevertheless, limited image contrast and relatively high radiation exposure (physical half-life of 124I: 4 days) have to be taken into account. Asymmetric receptor binding may possibly reflect pathologic changes in schizophrenia.

Pharmacokinetics of levamisole in broiler breeder chickens

The pharmacokinetics of levamisole was studied in 20 broiler breeder chickens (chickens that give eggs to breed broilers). A single dose of levamisole (40 mg/kg) was administered orally or intravenously to chickens before the onset of egg production, prelay (age = 22 weeks), and repeated at the peak of egg production (age = 32 weeks). A high-pressure liquid chromatographic with ultraviolet detection method (HPLC-UV) was used for quantification of levamisole in plasma. Using compartmental analysis, levamisole followed a three-compartmental open model with mean values of alpha = 0.1224 and 0.4968, beta = 0.01663 and 0.01813, gamma = 0.002 and 0.002/min at the prelay and at the peak of egg production periods, respectively. The mean values for volume of distribution at steady state (V(ss)), determined by compartmental analysis, were significantly different for prelay and peak of egg production (8.358 and 13.581 mL/kg), respectively.

Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen

Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic-pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites. Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m(2); 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection. The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m(2) and 211 l/m(2), respectively. The intrapatient variability (22-28%) was far lower than the interindividual variability (33-88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs. All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant.

Interconversion Pharmacokinetics of Simvastatin and its Hydroxy Acid in Dogs: Effects of Gemfibrozil

To characterize the pharmacokinetics of simvastatin (SV) and simvastatin acid (SVA), a lactone-acid pair known to undergo reversible metabolism, and to better understand mechanisms underlying pharmacokinetic interactions observed between SV and gemfibrozil. Pharmacokinetic studies were conducted after intravenous administration of SV and SVA to dogs pretreated with a vehicle or gemfibrozil. In vitro metabolism of SVA in dog hepatocytes as well as in vitro hepatic and plasma conversion of SV/SVA were investigated in the absence and presence of gemfibrozil. In control animals, the irreversible elimination clearances of SV (CL10) and SVA (CL20) were 10.5 and 18.6 ml min(-1) kg(-1), respectively. The formation clearance of SVA from SV (CL12 = 4.8 ml min(-1) kg(-1)) was 8-fold greater than that of SV from SVA (CL21 = 0.6 ml min(-1) kg(-1)), and the recycled fraction was relatively minor (0.009). In gemfibrozil-treated animals, CL10 was essentially unchanged, whereas CL12, CL20, CL21, and recycled fraction were significantly decreased to 2.9, 9, 0.14 ml min(-1) kg(-1), and 0.003, respectively. In control dogs, values for real volume of distribution at steady state (Vss,real) of SV (2.3 L kg(-1)) were much larger than the corresponding values of SVA (0.3 L kg(-1)). Gemfibrozil treatment did not affect Vss,real of either SV or SVA. In dog hepatocytes, gemfibrozil modestly affected the formation of CYP3A-mediated oxidative metabolites (IC50 > 200 microM) and beta-oxidative products (IC5) approximately 100 microM), but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of an SVA beta-oxidation product (IC50 = 18 microM). In in vitro dog and human liver S9 and plasma, hydrolysis of SV to SVA was much faster than that of SVA to SV. Gemfibrozil (250 microM) had a minimal inhibitory effect on the hydrolysis of either SV to SVA or SVA to SV in dog and human liver S9, but had a significant ( approximately 60%) inhibitory effect on the SV to SVA hydrolysis in both dog and human plasma. In dogs, the interconversion process favored the formation of SVA and was less efficient than the irreversible elimination processes of SV and SVA. Treatment with gemfibrozil did not affect the distribution of SV/SVA, but rather affected the elimination of SVA and the SV/SVA interconversion processes. Gemfibrozil decreased CL20 and CL21 likely via its inhibitory effect on the glucuronidation of SVA, and not on the CYP3A-mediated oxidative metabolism of SV or SVA, the beta-oxidation of SVA, nor the SVA to SV hydrolysis. The decrease in CL12 might be due in part to the inhibitory effect of gemfibrozil on SV to SVA hydrolysis in plasma. Similar rationales may also be applicable to studies in humans and/or other statin lactone-acid pairs.

Marked variation in oxycodone pharmacokinetics in infants

The pharmacokinetics of oxycodone (13-hydroxy-7,8-dihydrocodeinone) has been studied in adults and in children who are older than 6 months but there is no information on the disposition of oxycodone in neonates and young infants. The aim of this study was to study the pharmacokinetics of oxycodone in infants varying in age from 0 to 6 months. Twenty-two infants undergoing surgery were given postoperatively an intravenous bolus of 0.1 mg.kg(-1) of oxycodone hydrochloride. Ten of the patients were younger than 1 week (group 1), six from 1 week to 2 months (group 2) and six from 2 to 6 months (group 3). Plasma samples were collected for the analysis of oxycodone concentrations up to 24 h. Pharmacokinetics were characterized by noncompartmental methods. The median (range) values for the clearance (Cl) were 9.9 (2.3-17.2), 20.1 (3.7-40.4) and 15.4 (14.8-80.2) ml.min(-1).kg(-1) in the above three groups. The values for volume of distribution at steady-state were 3.3 (1.9-4.7), 5.6 (1.3-8.5) and 3.2 (1.8-6.0) l.kg(-1) and for elimination half-life (t(1/2)) 4.4 (2.4-14.1), 3.6 (1.6-11.6) and 2.0 (0.8-3.9) h, respectively. Both Cl (r = 0.46) and half-life (r = -0.46) were correlated to the age of the patient (P < 0.05). There were 13 patients who were on mechanical ventilation at the time of oxycodone administration. None of the spontaneously breathing infants had hypoventilation which required assistance during the study. The values for Cl and t(1/2) varied greatly between the subjects. This variability was most pronounced in the two youngest groups. Routine dosing of oxycodone in young infants may be dangerous. The dose of oxycodone must be titrated individually.

Cremophor EL releases cyclosporin A adsorbed on blood cells and blood vessels, and increases apparent plasma concentration of cyclosporin A

We examined the influence of cremophor EL (crEL) on the disposition kinetics of CyA in rats. A dose of 10 mg/kg of CyA in a volume of 750 μL containing 4.3, 16 or 30% concentration of crEL was intravenously administered over 1 min to rats. The values of distribution volume at the steady-state (Vd ss) and total clearance (CL tot) of CyA in the presence of increasing amounts of crEL were decreased to about 1/3–1/5 of those with 4.3% crEL, in a crEL concentration-dependent manner. The values of blood to plasma concentration ratio (RBP) and the apparent tissue to plasma concentration ratio ( K p,app) of CyA with 30% crEL were both only about 1/2 of those of CyA with 4.3% crEL. Next, rats were intravenously given 30% crEL solution at 30 min after an intravenous administration of CyA (10 mg/kg) with 4.3% crEL. Subsequently, the blood and plasma concentrations of CyA rose significantly to 2.4 and 4.7 times those seen when i.v. 30% crEL was not given, respectively. In an in vitro study, we found that the uptake of CyA by red blood cells is inhibited by crEL, and that CyA adsorbed on the inner surface of blood vessels after the administration of CyA is released by crEL. The disposition kinetics of CyA is altered by i.v. administration in combination with the surfactant vehicle crEL, in a crEL concentration-dependent manner.

Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates

To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery. Observational study in a level III referral center. Pharmacokinetic estimates from 14 neonates undergoing ECMO were compared with findings from a previous study in 0- to 3-year-olds after noncardiac major surgery using a nonlinear mixed effect model. A one-compartment linear disposition model with zero-order input (infusion) and first-order elimination was used to describe all data. Clearance in neonates (age <7 days) at the start of ECMO (2.2 l per hour per 70 kg) was lower than that in postoperative neonates (10.5 l per hour per 70 kg) but increased rapidly (maturation half-life 30 and 70 days, respectively) and equaled that of the postoperative group after 14 days. Clearance was affected by size and age only. Exchange transfusion, when used, contributed only 1.1% (CV 46%) of total clearance. Distribution volume increased with age and was 2.5 times (CV 102%) greater in ECMO children than in postoperative children. The between-subject variability values for volume of distribution and clearance were 49.4% and 38.7%. Weight and age information explained 83% of the overall clearance variability and 60% of overall distribution volume variability. Morphine clearance is reduced in infants requiring ECMO, possibly reflecting severity of illness. Clearance maturation on ECMO is rapid and normalizes within 2 weeks. Initial morphine dosing may be guided by age and weight, but clearance and distribution volume changes (and their variability) during prolonged ECMO suggests that morphine therapy should be subsequently guided by clinical monitoring.

Quantification of [ 18F]diprenorphine kinetics in the human brain with compartmental and non-compartmental modeling approaches

6- O-(2-[ 18F]fluoroethyl)-6- O-desmethyldiprenorphine ([ 18F]FDPN) is a nonselective opiate ligand that binds to postsynaptic μ, κ and δ opiate receptors. Due to the longer half-life of F-18, compared to C-11, labeling DPN with F-18 allows for alternative experimental protocols and potentially the evaluation of endogenous opioid release. The applicability of this compound to assorted experimental protocols motivated the evaluation of [ 18F]FDPN kinetics with compartmental and non-compartmental models. The results indicate that a two-tissue compartmental model best characterizes the data obtained following a bolus injection of [ 18F]FDPN (120-min scanning protocol). Estimates of distribution volume (DV) were robust, being highly correlated for the one-tissue compartmental model as well as the invasive Logan model and the basis function method. Furthermore, the DV estimates were also stable under a shortened protocol of 60 min, showing a significant correlation with the full protocol. The binding potential (BP) values showed more variability between methods and in some cases were more sensitive to protocol length. In conclusion, this evaluation of [ 18F]FDPN kinetics illustrates that DV values can be estimated robustly using compartmental modeling, the basis function method or the invasive Logan modeling approach on a volume of interest level. BP values were also found to correlate with DV values; however, these results should be interpreted with the understanding that specific binding in the reference region (occipital region) may exist.

Kinetics and EEG Effects of Midazolam during and after 1‐Minute, 1‐Hour, and 3‐Hour Intravenous Infusions

The objective of this study was to evaluate the kinetics and dynamics of midazolam when administered by three different infusion schemes, using electroencephalography to measure pharmacodynamic effects. In a three-way crossover study, 8 volunteers received midazolam (0.1 mg/kg) by constant-rate intravenous infusion. The durations of midazolam infusions for the three trials were 1 minute, 1 hour, and 3 hours. Plasma midazolam concentrations and electroencephalographic (EEG) activity in the 13- to 30-Hz range were monitored for 24 hours. Based on separate analysis of each subject-trial, mean values for volume of distribution and distribution or elimination half-life did not significantly vary. Central compartment volume and clearance differed among the three midazolam infusion trials; however, the magnitude of change was small. EEG activity in the 13- to 30-Hz range significantly increased for all three midazolam infusion trials. Plots of midazolam plasma concentration versus pharmacodynamic EEG effect for the 1-hour and 3-hour infusion trials did not reveal evidence of either counterclockwise or clockwise hysteresis. Plots from the 1-minute infusion trial demonstrated counterclockwise hysteresis, consistent with an equilibration effect-site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model. Analysis of all three infusion trials together yielded the following mean estimates: maximum EEG effect, 16.3% over baseline; 50% maximum effective concentration, 31 ng/mL; and an apparent rate constant for drug disappearance from the effect compartment which approached infinity. Despite the delay in effect onset during the 1-minute midazolam infusion, midazolam infusions in duration of up to 3 hours produce CNS sedation without evidence of tolerance.

Cluster analysis in kinetic modelling of the brain: a noninvasive alternative to arterial sampling

In emission tomography, quantification of brain tracer uptake, metabolism or binding requires knowledge of the cerebral input function. Traditionally, this is achieved with arterial blood sampling. We propose a noninvasive alternative via the use of a blood vessel time–activity curve (TAC) extracted directly from dynamic positron emission tomography (PET) scans by cluster analysis. Five healthy subjects were injected with the 5HT 2A-receptor ligand [ 18F]-altanserin and blood samples were subsequently taken from the radial artery and cubital vein. Eight regions-of-interest (ROI) TACs were extracted from the PET data set. Hierarchical K-means cluster analysis was performed on the PET time series to extract a cerebral vasculature ROI. The number of clusters was varied from K = 1 to 10 for the second of the two-stage method. Determination of the correct number of clusters was performed by the ‘within-variance’ measure and by 3D visual inspection of the homogeneity of the determined clusters. The cluster-determined input curve was then used in Logan plot analysis and compared with the arterial and venous blood samples, and additionally with one of the currently used alternatives to arterial blood sampling, the Simplified Reference Tissue Model (SRTM) and Logan analysis with cerebellar TAC as an input. There was a good agreement ( P < 0.05) between the values of Distribution Volume (DV) obtained from the K-means-clustered input function and those from the arterial blood samples. This work acts as a proof-of-principle that the use of cluster analysis on a PET data set could obviate the requirement for arterial cannulation when determining the input function for kinetic modelling of ligand binding, and that this may be a superior approach as compared to the other noninvasive alternatives.

Quantitative assessment of P-glycoprotein function in the rat blood–brain barrier by distribution volume of [11C]verapamil measured with PET

The blood–brain barrier (BBB) is a functional barrier that hampers the delivery of various drugs to the brain by its physicoanatomical properties and by the presence of ATP-driven drug efflux pumps, such as P-glycoprotein (P-gp). The aims of this study were (1) to study whether the distribution volume (DV) is useful for quantification of (labeled) P-gp substrate kinetics over the BBB and (2) to study how brain DV is affected by P-gp modulation. We measured the kinetics of the P-gp substrate [11C]verapamil (0.1 mg/kg) in rat brains using positron emission tomography (PET) and arterial blood sampling. Cyclosporin A (CsA) at 0, 10, 15, 25, 35, and 50 mg/kg of body weight was used as a P-gp modulator. The [11C]verapamil kinetics were very well described by DV, computed by noncompartmental Logan analysis. Logan analysis resulted in excellent fits of dynamic PET data, revealing the reversible behavior of [11C]verapamil and its associated DV. The DV in unmodulated rats was 0.65 ml/ml ± 0.23 (mean ± SD). After modulation with 10, 15, 25, 35, and 50 mg/kg of CsA, DV values increased to 0.82 ± 0.06, 1.04 ± 0.20, 2.85 ± 0.51, 2.91 ± 0.64, and 3.77 ± 1.23, respectively. The [11C]Verapamil kinetics were saturable at modulation levels above 25 mg/kg of CsA. The data fitted well by a four-parameter Hill plot (R2 = 0.79). In conclusion, the DV of [11C]verapamil is a valid and potent tool to measure the kinetics of (labeled) P-gp substrates in vivo at the BBB. The brain DV of [11C]verapamil increases dose dependently by P-gp modulation. Quantitative insight into in vivo P-gp modulation may be a promising step toward assessment of P-gp substrate delivery to human brains.

Pharmacokinetics and allometric scaling of levormeloxifene, a selective oestrogen receptor modulator.

The pharmacokinetics of a new selective oestrogen receptor modulator levormeloxifene was investigated in mice, rats, cynomolgus monkeys and humans by compartmental pharmacokinetics. Levormeloxifene was administered as an oral solution in all studies. Allometric scaling was used to predict human pharmacokinetic parameters and the performance of the approach was evaluated. Mean values of clearance confounded by F(CL/F) were 0.073, 0.29, 3.18 and 2.4 l/h in mice, rats, monkeys and humans, respectively. Values of distribution volume at steady state confounded by F(V(ss)/F) were 0.073 and 7.5 l in mice and rats. In monkeys, values of the central volume F(V(c)/F) and volume at steady state F(V(ss)/F) were 28.9 and 57.9 l, respectively. In humans, values of V(c)/F and V(ss)/F were 106 and 587 l, respectively. Predicted CL/F and V(ss)/F showed a linear relationship when plotted vs BW on a log-log scale; for CL/F, r was 0.95-0.98 and for V(ss)/F, r was 0.99. Using allometric scaling the predicted human V(ss)/F deviated 3-fold from the experimentally determined values. Observed values of CL/F deviated 21-25 fold from the predicted, the latter depending on the scaling method. Confidence intervals for the predicted parameters showed major lack of precision for all the allometric scaling methods.