Initial Distribution Volume Research Articles

Transport of D-glucose and 2-fluorodeoxyglucose across the blood-brain barrier in humans.

The deoxyglucose method for calculation of regional cerebral glucose metabolism by PET using 18F-2-fluoro-2-deoxy-d-glucose (FDG) requires knowledge of the lumped constant, which corrects for differences in the blood-brain barrier (BBB) transport and phosphorylation of FDG and glucose. The BBB transport rates of FDG and glucose have not previously been determined in humans. In the present study these transport rates were measured with the intravenous double-indicator method in 24 healthy subjects during normoglycemia (5.2 +/- 0.7 mM). Nine subjects were restudied during moderate hypoglycemia (3.4 +/- 0.4 mM) and five subjects were studied once during hyperglycemia (15.0 +/- 0.7 mM). The global ratio between the unidirectional clearances of FDG and glucose (K1*/K1) was similar in normoglycemia (1.48 +/- 0.22), moderate hypoglycemia (1.41 +/- 0.23), and hyperglycemia (1.44 +/- 0.20). This ratio is comparable to what has been obtained in rats. We argue that the global ratio is constant throughout the brain and may be applied for the regional determination of LC. We also determined the transport parameters of the two hexoses from brain back to blood and, assuming symmetrical transport across the BBB, we found evidence of a larger initial distribution volume of FDG in brain (0.329 +/- 0.236) as compared with that of glucose (0.162 +/- 0.098, p < 0.005). The difference can be explained by the very short experimental time, in which FDG may distribute both intra- and extracellularly, whereas glucose remains in a volume comparable to the interstitial fluid of the brain.

Repeated Doses of Rocuronium Bromide Administered to Cirrhotic and Control Patients Receiving Isoflurane

Steroid muscle relaxants often display pharmacodynamic changes in patients with cirrhosis because of alterations in elimination processes. Rocuronium is a new steroid muscle relaxant possibly eliminated through the liver. This study was designed to compare rocuronium pharmacodynamics and pharmacokinetics in cirrhotic and healthy patients. Rocuronium was administered to 26 cirrhotic patients and 24 control subjects anesthetized with isoflurane for an elective procedure. Patients were randomly allocated to received an initial dose of rocuronium: 120, 180, 250, or 300 micrograms.kg-1. Dose-response curves were established, and ED50 was calculated. Preselected maintenance doses (75, 150, or 225 micrograms.kg-1) were administered at 25% recovery of twitch height to compare clinical duration of action. At the end of the procedure, relaxation was reversed in half of the patients, and the time course of recovery was compared in the two groups. Blood samples drawn during the procedure and after the last maintenance dose allowed pharmacokinetic analysis in six cirrhotic patients and six control subjects. ED50 of the initial dose was 144 micrograms.kg-1 in cirrhotic patients and 60 micrograms.kg-1 in control subjects, related to a higher initial volume of distribution (cirrhotic 78.5 +/- 31.7 ml.kg-1, control 29.8 +/- 17.3 ml.kg-1). Time from complementary dose to 25% recovery was longer in cirrhotic patients (41.0 +/- 20.7 min vs 30.2 +/- 9.7 min), but time course of action during maintenance was not statistically different in the two groups. In cirrhotic patients receiving five maintenance doses or more, prolongation of the duration of action with successive maintenance doses could be statistically demonstrated. Spontaneous recovery was delayed in cirrhotic patients, because of impaired elimination processes: greater volume of distribution at steady-state (264 +/- 92 vs. 151 +/- 59 ml.kg-1); trend toward a lower clearance (189 +/- 60 vs. 296 +/- 169 ml.min-1). Rocuronium pharmacodynamics are moderately altered by cirrhosis, possible because of pharmacokinetic alterations. Individual variability in response to rocuronium is great, and dosage should be carefully titrated to that required.

Pharmacokinetics and Interspecies Scaling of Recombinant Human Factor VIII

Recombinant human (rh) factor VIII is a glycoprotein consisting of multiple polypeptides with relative mobilities (Mr) ranging from 80,000 to 210,000. It is produced in mammalian cells. Single-dose intravenous pharmacokinetic studies were conducted with rh factor VIII (Kogenate rh Antihemophilic Factor, Miles, Inc.) in male mice (21.0–25.8 g) and rats (252.0–254.2 g). Each species received 400 IU/kg, and blood was collected up to 12 hr (mice) or 32.5 hr (rats) post-dose. Immunoreactive factor VIII concentrations in plasma were quantified by a sensitive and specific ELISA. In both species, the disposition profiles were described by the sum of two exponentials. The pharmacokinetics of rh factor VIII in mouse were as follows: clearance, 27.7 ml/hr/kg; initial volume of distribution, 72 ml/kg; steady-state volume of distribution, 148 ml/kg; and terminal half-life, 4.1 hr. In rat, the mean estimates were as follows: clearance, 16.0 ml/hr/kg; initial volume of distribution, 41 ml/kg; steady-state volume of distribution, 125 ml/kg; and terminal half-life, 5.5 hr. These pharmacokinetic parameters for rh factor VIII in animals and human rh factor VIII pharmacokinetic parameters from the literature were evaluated to determine if the parameters can be represented by the allometric relationship,Y = aWb, whereYis the pharmacokinetic parameter, andWis body weight. The following allometric relations were obtained for rh factor VIII: clearance (ml/hr) = 10.4W0.69, half-life (hr) = 7.5W0.18, initial volume of distribution (ml) = 43.6W1.04, and steady-state volume of distribution (ml) = 99.1W0.84. The allometric exponents for each parameter conformed to theory and were within the range of values commonly observed for xenobiotics and therapeutic proteins. These studies suggest that the pharmacokinetics of rh factor VIII in laboratory animals are predictive of the disposition in humans despite the complex nature of its biological interactions and the chemical diversity of the purified material.

Does the Initial Distribution Volume of Glucose Reflect the Central Extracellular Fluid Volume Status in Critically ill Patients?

&lt;i&gt;Objective:&lt;/i&gt; Our experimental studies have indicated that the initial distribution volume of glucose (IDVG) has potential to evaluate the central extracellular fluid (ECF) volume status in the body. The purpose of the present study was to compare the IDVG and cardiac output (CO) in critically ill patients with or without expansion of the central ECF volume and to test whether a larger IDVG is observed during the presence of increased central ECF volume than during the absence of it. &lt;i&gt;Design and Setting:&lt;/i&gt; The study was prospective and was conducted in the intensive care unit, University of Hirosaki Hospital, after approval of the institutional ethical committee. &lt;i&gt;Patients:&lt;/i&gt; Fourteen patients with accumulation of the central ECF volume (the accumulation group) and 29 patients without it (the non-accumulation group) were studied. &lt;i&gt;Interventions:&lt;/i&gt; Glucose 5 g was infused over 30 s when the patients’ hemodynamic states were relatively stable. Blood samples were taken immediately before infusion and during 7 min post-infusion. Thermodilution CO was also measured before each glucose challenge. A total of 81 comparisons were performed. &lt;i&gt;Measurements and Results:&lt;/i&gt; The IDVG was calculated using a one-compartment model. A linear correlation was obtained between the IDVG and CO in the non-accumulation group (r = 0.89, n = 54, p &lt; 0.001). The IDVG-CO ratio was higher in the accumulation group than in the non-accumulation group (p &lt; 0.01). The increased plasma glucose concentrations at 3 min postinfusion were inversely proportional to the IDVG (r = -0.90, n = 81, p &lt; 0.001). &lt;i&gt;Conclusions:&lt;/i&gt; Results demonstrated that a larger IDVG was obtained during accumulation of the central ECF volume and support the hypothesis that the IDVG reflects the central ECF status in critically ill patients characterized in our study, even though CO influences the IDVG.

Changes in Vancomycin Pharmacokinetics in Critically Ill Infants

We aimed to assess the pharmacokinetics of vancomycin in critically ill infants, and to evaluate the standard recommended dose of 10 mg/kg 6 hourly. All infants admitted to the Baragwanath Hospital ICU who had arterial lines in situ, and for whom vancomycin 10 mg/kg 6 hourly was prescribed for an infective insult and who had parental consent, were included in the study. Vancomycin was infused over 60 minutes. Serum samples were taken immediately before the dose and at 30, 60, 120 and 300 minutes after the end of the vancomycin infusion, on days 2 and 8 of therapy. Extrapolated peak concentration (Cmax), trough concentration (Cmin), apparent volume of distribution (Vd), elimination half-life (t1/2el) and clearance (CL) were determined for each patient. Day 2 values were compared with those of day 8. Day 2 serum concentrations were assayed on 20 patients and day 8 concentrations in 15. The mean vancomycin Vd on day 2 (0.81 l/kg) was significantly (P = 0.007) larger than that on day 8 (0.44 l/kg). The change in Vd resulted in a significant change in mean Cmax (29.1 vs 35.5 micrograms/ml) (P = 0.02) and mean t1/2el (5.3 vs 3.4h) (P = 0.01) over the treatment period. Critically ill infants displayed a large initial volume of distribution which probably resulted from aggressive fluid resuscitation. This also results in a large variation in other pharmacokinetic parameters, namely Cmax and t1/2el. Although the routine monitoring of vancomycin serum concentrations remain controversial, we feel that in view of these large pharmacokinetic variations, the critically ill infant is a specific group where monitoring of vancomycin serum levels is indicated.

Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients.

Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three-compartment model and linear kinetics. After a single iv bolus, the mean initial volume of distribution (V1) was 0.481 l.kg-1, and the steady-state volume of distribution (Vss) was 2.16 l.kg-1. The distribution (t1/2 alpha) and elimination (t1/2 beta) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml.min-1.kg-1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CVintra) as it was between patients (CVinter). The steady-state trough plasma concentration (Cmin obs) ranged from 4.8 to 30 mg.l-1 (mean 16.0 mg.l-1 and median 14.3 mg.l-1). Peak concentrations (Cmax obs) ranged from 8.35 to 45 mg.l-1 (25.4 mg.l-1, and median 23.3 mg.l-1). The values of V1 and Vss were similar to those obtained after a single dose. For V1, the mean was 0.333 l.kg-1. The mean Vss was 2.68 l.kg-1, with a CVintra of 12.6 to 56% and a CVinter of 13.2%. A shorter distribution half-life t1/2 alpha was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t1/2 beta and the mean residence time became longer due to a decrease in clearance. For t1/2 beta the mean value was 16.3 h. The mean MRT was 21.9 h, CVintra 9.19 to 48.5%, and the CVinter 35.3%. The mean clearance was 2.16 ml.min-1.kg-1, CVintra 7.28 to 25.5%, and the CVinter 20.4%. This value is 50% lower than after a single dose. Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.

Pharmacokinetics, tissue distribution, and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin.

Antibody ZME-018 is directed against the gp240 glycoprotein on the surface of more than 80% of human melanoma cell lines and fresh biopsy specimens. Previous studies in our laboratory described the in vitro cytotoxicity and specificity of an immunoconjugate composed of mAb ZME-018 and the plant toxin gelonin. The present study described the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xenograft/nude mouse models. Pharmacokinetic studies of 125I-labeled ZME-018 and ZME-gelonin demonstrated a shorter terminal-phase plasma half-life of the immunoconjugate than native ZME (20.6 h compared to 41.3 h). The initial volume of distribution of the ZME-gelonin was also higher compared to that of ZME alone (2.85 ml compared to 1.94 ml) suggesting an enhanced distribution of the conjugate outside the vasculature. The corresponding area under the concentration/time curve for the ZME-gelonin conjugate was 40% lower than that of ZME alone (80.8 compared to 139.6 microCi.ml-1 x min). In nude mice bearing well-developed human tumor A375 melanoma xenografts, administration of 125I-labeled ZME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9 +/- 0.5 and 1.5 +/- 0.6 respectively by 72 h. Compared with ZME, ZME-gelonin conjugate caused an increase in the content of radiolabel in kidney, spleen and liver. Treatment of nude mice bearing well-developed (150 mm3) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelonin, or saline resulted in suppression of tumor growth in the immunotoxin group but virtually no retardation of tumor growth in the control groups. Using a murine model for a rapidly growing lethal metastatic human melanoma, treatment with ZME-gelonin resulted in a mean survival of 44 days, 213% increase in mean survival time compared with the saline treatment (14.2 +/- 2 day survival). Given these encouraging results, we are proceeding with further preclinical development of this immunotoxin.

Permeability of the developing blood-brain barrier to 14C-mannitol using the rat in situ brain perfusion technique

The brain penetration of 14C-mannitol was investigated using a bilateral in situ brain perfusion technique followed by capillary depletion analysis. This technique measures the uptake of slowly penetrating solutes in the absence of the systemic circulation, and separates accumulation in brain endothelial cells from uptake into brain parenchyma. Penetration of 14C-mannitol was linear up to 30 min in rats aged 1, 2, 3 weeks and in adults. The brain mannitol space was higher in 1-week-old neonatal rats compared with adults ( ( P < 0.05) and was due to a greater initial volume of distribution ( V i) for mannitol in the neonates, and not due to an elevated transfer rate ( K in) Thirty percent of mannitol in the neonatal brain was associated with the capillary containing fraction, whereas in the adult only 13% was found in this fraction. This suggests that the permeability of the blood-brain barrier to mannitol does not change significantly with development but that more mannitol is associated with endothelial cells in the neonate. An investigation of 14C-glycine uptake was also carried out, and unlike mannitol the Kin was greater in the neonate compared to the adult suggesting an elevated rate of transfer for this amino acid into the neonatal rat brain.

On-Line Estimation and Prediction of Urea Kinetics during Hemodialysis: A Simulation Approach

A new method for the on-line estimation of urea kinetic parameters from blood urea concentration (BUN) continuously measured during a dialysis session is proposed. The method, based on the variable-volume double-pool model, is evaluated through a simulation approach in order to easily consider a large set of well-controlled test conditions. The model is characterized by six parameters, knowledge of which enables early prediction of the end dialysis urea concentration and the dose of dialysis. The sensitivity of the model predicted BUN with respect to the parameters was first analyzed to investigate which can be reliably estimated from blood urea measurements taken at a suitable rate. This analysis showed that the model predicted BUN is highly sensitive to the initial blood urea concentration and to the dialyzer clearance, normalized with respect to the total initial distribution volume, while it is scarcely influenced by the normalized ultrafiltration and urea generation rates. The new on-line estimation technique keeps these two last parameters constant and takes advantage of an original analytic solution of the second order urea kinetics. The results of the estimation process on realistic simulated data showed that the proposed method provides early and reliable estimates of the normalized clearance and of the end dialysis concentration. The transcellular mass transfer coefficient and the intra-extra cellular volume ratio can also be estimated, although with less accuracy. Moreover, it was shown that the use of the single-pool model, instead of the double-pool one, provides systematic errors on the estimates.

Sensitivity analysis for estimating urea kinetics parameters during hemodialysis

In this paper a time-varying volume, double-pool urea kinetics model is considered and a sensitivity analysis is carried out to determine those patient parameters that have greater influence on the time course of blood urea nitrogen concentration (BUN) during and between dialysis treatment. The model parameters include the urea generation rate, the initial distribution volume of the urea, the ratio between intracellular and extracellular volumes, and the mass transfer coefficient between the two pools. The analysis demonstrates that BUN is highly sensitive to the urea generation rate and total distribution volume whereas it is influenced by the remaining parameters to a much lesser extent. In addition, the location of the absolute maxima of BUN sensitivity functions suggests the rational placement of a reduced number of blood samples that may still allow sufficiently accurate estimates for the parameters of clinical interest, such as the urea generation rate, total distribution volume, and the ratio between intracellular and extracellular volumes. This conclusion has been confirmed by simulation studies where parameter estimation has been performed with a varying number of observation points.

Does the initial distribution volume of glucose reflect plasma volume after haemorrhage in dogs?

To test the hypothesis that the initial distribution volume of glucose (IDVG) reflects plasma volume, the relationship between the IDVG and indocyanine green (ICG) assessments of plasma volume (Vd-ICG) were evaluated simultaneously both before and after induced haemorrhage (30 ml.kg-1) in eight mongrel dogs. The IDVG and the Vd-ICG were calculated with a one-compartment model from repeated measurements of plasma glucose three to seven minutes, and of plasma ICG three to nine minutes after simultaneous infusions of both glucose 100 mg.kg-1 and ICG 0.5 mg.kg-1. The IDVG calculated with a one-compartment model (IDVG-OCM) was also compared with a two-compartment model within 15 min (IDVG-TCM) on nine occasions among a total of 12 determinations. Using Bland and Altman analysis to compare the two analytical models, the IDVG-OCM tends to overestimate the IDVG-TCM by an average of 0.04 L. Although the IDVG-OCM was two to three times larger than the Vd-ICG at each corresponding point, a correlation was obtained between the IDVG-OCM and the Vd-ICG before and after induced haemorrhage (r = 0.85, n = 16, P < 0.001). We conclude that the IDVG reflects plasma volume in normal and hypovolaemic dogs, although the IDVG cannot be used directly to estimate plasma volume.

Changes in the initial distribution volume of glucose and plasma volume following volume challenge in dogs.

This study aimed to test the hypothesis that the initial distribution volume of glucose (IDVG) is correlated with plasma volume determined by indocyanine green (ICG) following colloidal fluid challenges. The IDVG was also compared with cardiac output (CO) as measured by the conventional thermodilution method. The study was prospective and was conducted in the animal laboratory, University of Hirosaki School of Medicine, after approval of the institutional animal experiment committee. Thirteen mongrel dogs of either sex, weighing 9.0-14.5 kg, were the subjects of the study. They were anesthetized with pentobarbital and paralyzed with pancuronium. 30 ml x kg(-1) of 3% dextran in lactated Ringer's solution was given twice to induce a hypervolemic state. In each stage of the fluid loading, the IDVG, plasma volume and CO were measured simultaneously. The IDVG was measured following an injection of glucose (100 mg x kg(-1)) by repeated determinations of plasma glucose (3-7 min) with a one-compartment model, and plasma volume was assessed similarly following ICG (0.5 mg x kg(-1) injection. A closer correlation was observed between the IDVG and plasma volume (r = 0.79, p < 0.001) than between the IDVG and CO (r = 0.48, p < 0.01). The IDVG correlates with plasma volume following volume challenge in dogs. CO did not show a consistent change following volume challenge. The IDVG may have the potential as an indicator to presume the fluid volume in the body, even though the IDVG cannot be used directly to estimate plasma volume.

Metabolic clearance of atrial natriuretic factor in ovine pregnancy

Plasma atrial natriuretic factor (ANF) is normally released into the circulation primarily by volume expansion and atrial distension, but we have shown that plasma ANF is elevated in pregnant sheep before volume expansion. Because alterations in the metabolic clearance of ANF could lead to elevated plasma ANF levels, the present study was designed to determine the pharmacokinetics of plasma ANF in pregnant sheep. Chronically instrumented nonpregnant and pregnant sheep received intravenous injections of monoiodinated human ANF (125I-hANF). Plasma decay curves of 125I-hANF followed a biexponential function in both groups. High-performance liquid chromatography (HPLC) revealed the accumulation of smaller degradation products by 2 min postinjection, and by 30 min no intact ANF was present. Because HPLC identification of ANF and its metabolites was shown to be more efficient than precipitation with 10% trichloroacetic acid (TCA) or extraction by Sep-Pak cartridges, ANF kinetic parameters were calculated from HPLC-corrected plasma decay curves. Injected ANF was rapidly distributed in an initial distribution volume (IDV) that was expanded in pregnant sheep. Metabolic clearance rate (MCR) was greater in pregnant sheep (2.8 +/- 0.3 vs. 6.8 +/- 1.2 l/min, P = 0.002), while plasma half-life (t1/2) was not altered (2.2 +/- 0.5 vs. 2.4 +/- 0.4 min). The data demonstrate that during pregnancy, the t1/2 of ANF is not altered but the MCR of ANF is enhanced. These findings imply that plasma ANF is increased by mechanisms other than reduced clearance in pregnant sheep.

Kinetic study of atrial natriuretic peptide in patients with idiopathic dilated cardiomyopathy: evidence for resistance to biologic effects of the hormone even in patients with mild myocardial involvement.

Atrial natriuretic peptide (ANP) kinetics was studied in 12 patients with idiopathic dilated cardiomyopathy at different sodium excretion (30-175 mmol/day) and variable degrees of hemodynamic dysfunction [New York Heart Association (NYHA) class range I-III] to investigate whether differences in renewal and distribution of this hormone (as compared with those of a control group) play a role in pathogenesis and evolution of heart failure. [125I]Labeled ANP was injected as a bolus, and a high-performance liquid chromatography (HPLC) procedure was used to purify the labeled hormone in venous plasma samples collected for < or = 50 min after injection; the main ANP kinetic parameters were then derived from the disappearance curve of the labeled hormone. As in controls, a positive linear regression between ANP metabolic clearance rate (MCR, ml/min/m2) values and daily urinary excretion of sodium (NaUE, mmol/day) was noted in patients. The different linear regression coefficients between normal subjects (MCR = 365 +/- 8.08 NaUE, r = 0.986, p < 0.0001) and patients (MCR = 497 + 18.5 NaUE, r = 0.867, p = 0.001) indicate that in patients a higher peptide clearance rate is needed to obtain the same biologic effect (sodium excretion) and suggest that resistance to biologic effects of the hormone exists in patients at an early stage of disease (NYHA class I). When the efficiency of the ANP system in excreting sodium was expressed as the ratio of NaUE to ANP production rate (PR = MCR x ANP plasma concentration, microgram/day/m2) patients showed significantly lower values (p = 0.0126) than normal volunteers, thus confirming resistance to the hormone effects. Significantly lower values for ANP total distribution volume (16.5 +/- 8.4 L/m2), mean residence time in the sampling space (4.04 +/- 1.14 min), mean residence time in the body (7.25 +/- 2.13 min), and fewer recycles through the initial (sampling) space (0.27 +/- 0.16) were noted in patients, indicating an altered mechanism regulating distribution of the hormone. The positive correlations between ANP MCR (L/min/m2) values and cardiac index (CI, L/min/m2) (MCR = -1.24 + 1.17 CI, r = 0.689, p = 0.0092) and between initial distribution volume (IDV, L/m2) and CI (IDV = -11.2 + 6.85 CI, r = 0.730, p = 0.0046) in all patients indicate that hemodynamic factors contribute to the progressive reduction in MCR and IDV values throughout the progression of myocardial involvement.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood-to-lens Transport of Reduced Glutathione in an In Situ Perfused Guinea-pig Eye

Transport mechanisms of reduced glutathione (GSH) in intact eye are poorly understood. In this study, an in situ vascular eye perfusion (VEP) model was used to characterize the transport kinetics of circulating GSH into the aqueous humor and lens in guinea pigs. Radiolabeled [ 35S]GSH or [ 3H]GSH and [ 14C]sucrose (an extracellular space marker) were exposed to the blood-aqueous barrier up to 10 min, and uptake of tracers by the aqueous humor and lens was determined in the presence of different concentrations of unlabeled peptide as GSH, a gamma-glutamyl compound as a derivative of GSH (GSH monoethyl ester), and an inhibitor of gamma-glutamyl transpeptidase (GGT) activity. Plasma-aqueous and aqueous-lens compartmental unidirectional transport constant, K in, and the initial rapid volume of distribution. V i, were estimated by multiple-time-point graphic analysis. Our results indicated that both labeled GSH and sucrose entered the aqueous humor slowly at comparable rates with respective blood-aqueous K in values of 1·34 ± 0·12 and 1·25 ± 0·08 min -1 × 10 3. In contrast to blood-aqueous transport, GSH uptake by the lens was rapid, and the respective aqueous-lens K in values for labeled GSH and sucrose were 79·3 ±4·1 and 3·5 ± 0·7 min -1 × 10 3. Over 94% of plasma-derived GSH remained in its original molecular form of GSH in the lens, during the 10 min perfusion both with and without the GGT inhibitor, serine borate. The amount of [ 35S]GSH in lens anterior epithelium (dpm mg -1) was more than three times that of aqueous humor (dpm μl -1) within only 10 min of VEP. There was also significant accumulation of [ 35S]GSH in the interior cortex, as indicated by 10-min cortex/aqueous ratio of 0·65. A specific GGT independent GSH transport system was demonstrated in the lens in situ, with a K m of 26 ± 3 μM, and V max of 34 ± 3 pmol min -1 g -1 of whole lens tissue water. The lenticular influx of GSH was inhibited by GSH monoethyl ester with an affinity that was half that for GSH. It is concluded that: (a) uptake of plasma-derived GSH into the aqueous humor is by simple diffusion, and (b) cellular uptake of GSH by the lens is carrier-mediated via mechanism that is separate from the transpeptidation metabolic pathway.

Changes in the Initial Distribution Volume of Glucose and Plasma Volume after Fluid Challenge in Dogs

Changes in the Initial Distribution Volume of Glucose and Plasma Volume after Fluid Challenge in Dogs

Pharmacokinetic parameters of vancomycin for therapeutic regimens in neutropenic adult patients

Vancomycin (V) is widely used in neutropenic patients, though its kinetics are known in this type of patient. In the present study, ten patients were included: all of them received an intensive therapy for non-Hodgkin malignant lymphoma, Hodgkin disease, myeloma, acute leukemia, followed by an autologous bone marrow transplantation in 6 cases. All patients were neutropenic (100/mm 3). The pharmacokinetic study was done at the first V administration: 1000 mg V were injected as a 1-h infusion. Plasma V concentrations were measured by an enzyme immunoassay (EMIT®, Syva, France). V maximal and minimal concentrations were 61.3 ± 38.6 μg/ml and 1.69 ± 0.77 μg/ml, respectively. Total V clearance was 158 ± 51 ml/min, with a creatinine clearance of 141.2 ± 36.2 ml/min on test day. V plasma kinetics can be described by a biexponential model, with the following parameters: V dα ( I) V dβ ( I) T 1 2 β ( h) T 1 2 β ( h) , 22.9±11.4 39.1±12.2 0.39±0.33 2.94±0.84 These data show a 3-fold increase of initial volume of distribution and a shortened (3-fold) T 1 2 β , if compared to values obtained in normal subjects. Because the bactericidal effect is time dependent, there can be a risk of insufficient antibiotic effect throughout the day. Our data suggest that new therapeutic regimens are needed for these patients.

The metabolism of estrone sulfate in the female rhesus monkey

In order to study the metabolism of estrone sulfate in the adult female rhesus monkey, we gave four monkeys a pulse injection of [ 3H]estrone sulfate and obtained blood samples at 15, 30, 60, 120, 300, and 1,440 minutes after the pulse. All blood samples were analyzed for [ 3H]estrone sulfate. The mean ±SE for the initial volume of distribution was 4.6 ± 0.9 L. The mean metabolic clearance rate (MCR) was 42.0 ± 2.9 L/day. In addition, 2 monkeys were infused for 240 minutes with [ 3H]estrone sulfate and 5 monkeys were infused for 240 minutes with [ 3H]estrone sulfate/[ 14C]estrone. Three blood samples were obtained during the last hour of the infusions and analyzed for radioactivity as estrone sulfate, estrone, and estradiol, and MCRs, conversion ratios, and [ϱ] BB values were calculated. The mean ± SE for the MCR was 67.5 ± 8.3 L/day, and for the conversion ratio, estradiol to estrone sulfate was 0.054 ± 0.016. The mean [ϱ] BB value for estrone sulfate conversion to estrone was 43.6 ± 3.4% and for estrone conversion to estrone sulfate was 33.5 ± 6.6%. Thus estrone sulfate is cleared slowly and is converted to both estrone and estradiol. The hydrolysis of estrone sulfate to estrone is not significantly different than conversion of estrone to estrone sulfate. (Steroids 59: 270–273, 1994)

The initial distribution volume of glucose and cardiac output after haemorrhage in dogs.

The purpose of the study was to evaluate the role of insulin in glucose kinetics after glucose administration using an insulinogenic index to indicate the magnitude of insulin response. The initial distribution volume of glucose (IDV-G) was calculated with a one-compartment model from repeated measurements of plasma glucose concentration three to seven minutes after administration of 100 mg.kg-1 glucose. The IDV-G was compared with the insulin response and the thermodilution assessments of cardiac output, measured simultaneously both before and after induced haemorrhage (30 ml.kg-1 over 30 min) in 12 adult mongrel dogs. The plasma insulin concentration was measured during the procedure and insulinogenic indices were calculated. There was no correlation between the IDV-G and insulinogenic indices, but there was a correlation between the IDV-G and thermodilution cardiac output before and after induced haemorrhage (r = 0.85, n = 24, P < 0.001). We conclude that the initial distribution volume of glucose is an indication of cardiac output in normo- and hypovolaemic dogs. Modification of glucose kinetics by the insulin response to glycaemic stimuli was negligible in that short period of time.

Fate of circulating amino-terminal propeptide of type III procollagen in conscious pigs.

The amino-terminal propeptide of type III procollagen (PIIINP, M(r) 42,000) is a promising marker for the formation of type III collagen of granulation tissue in experimental and clinical studies. The disposal kinetics of circulating PIIINP is, however, almost unknown. In conscious pigs with a thoracic duct-venous shunt, 125I-labeled PIIINP was injected intravenously. The initial distribution volume was 2.2 liters, which was 1.7 times the plasma volume (P < 0.01). The disappearance curve was three-phased, with an initial steep decline (t1/2 58 min), followed by two slower phases (t1/2 239 min and 289 h). Consecutive gel filtrations showed that the initial slope of the plasma disappearance curve corresponded to the plasma clearance of the intact PIIINP. The initial plasma clearance was 26.5 ml plasma/min, whereas the urinary clearance was 8.7 ml plasma/min (P < 0.01). The other components of the plasma disappearance curve originated from the formation and disappearance of a high and a low molecular weight (MW) fraction as part of the degradation of PIIINP. The high MW fraction (approximately M(r) 90,000) was similar to a previously described, but not further characterized, PIIINP immunoreactive component. The existence of the low MW fraction (approximately M(r) 20,000) has not been reported before. The lymphatic recirculation of intact PIIINP was rapid, and the lymph-serum ratio was almost constant within 1 h of injection. We conclude that the t1/2 of circulating PIIINP is 58 min, that PIIINP escapes the circulation very quickly, and that the degradation of PIIINP includes at least two intermediary steps.