Blood Residence Time Research Articles

Liposomes with entrapped doxorubicin exhibit extended blood residence times

The blood residence time of liposomes with entrapped doxorubicin is shown to be significantly longer than for identically prepared empty liposomes. Liposomal doxorubin systems with a drug-to-lpid ratio of 0.2 (w/w) were administered at a dose of 100 mg lipid/kg. Both doxorubicin and liposomal lipid were quantified in order to assess in vivo stability and blood residence times. For empty vesicles composed of phosphatidylcholine (PC)/cholesterol (55:45, mole ratio) and sized through filters of 100 nm pore size, 15–25% of the administered lipid dose was recovered in the blood 24 h after i.v. injection. The percentage of the dose retained in the circulation at 24 h increased 2–3-fold when the liposomes contain entrapped doxorubicin. For 100 nm distearoyl PC/chol liposomal doxorubicin systems, as much as 80% of the injected dose of lipid and drug remain within the blood compartment 24 h after i.v. administration.

PH-sensitive, plasma-stable liposomes with relatively prolonged residence in circulation

Acid-sensitive liposomes composed of unsaturated phosphatidylethanolamine (PE) are efficient vehicles for cytoplasmic delivery of the target cells. We have recently shown that liposomes composed of dioleoyl-PE (DOPE) and dipalmitoylsuccinylglycerol DPSG retain the acid-sensitivity after exposure to human plasma. In the present work, we have extended these observations to investigate the role of ganglioside GM 1 on the blood residence time of these liposomes. Small ( d≈ 100 nm) unilamellar liposomes composed of DOPE and DPSG (4:1, molar ratio) became progressively less acid-sensitivie when increasing amounts of GM 1 were included in the lipid composition. However, partial sensitivity to acid (40–50% release of entrapped contents at pH 4) could be retained up to 5% GM 1, even for liposomes which had been exposed to human plasma. Inclusion of GM 1 in the lipid composition only slightly increased the release of entrapped contents in the presence of human plasma. The biodistribution of i.v. injected GM 1-containing liposomes was studied by following the entrapped 125I-labeled tyraminylinulin marker in Balb/c mice. Inclusion of up to 5% GM 1 showed a transient increase in the blood level and a concomitant decrease of liver and spleen uptake of liposomes. Thus, these liposomes are pH-sensitive, plasma-stable and show a relatively prolonged residence time in circulation. They are potentially significant drug carriers in vivo.

The effects of dose of elemental mercury and first-pass circulation time on exhalation and organ distribution of inorganic mercury in rats

The lung plays a major role in the removal of dissolved elemental mercury (Hg 0) from the bloodstream. During the first passage through the lung after an intravenous dose of Hg 0 dissolved in aqueous buffer, from 10 to 17% was exhaled depending on the dose (0.11 or 1.1 μg Hg/rat) and the injection site (jugular versus tail vein). Furthermore, evidence is presented that subsequent exhalation over the next 50 s, before the rats were killed and the mercury determined in the lung at that time, was largely Hg 0-extracted during the first pass. The total mercury extracted during the 60 s period was in the range of 40–49% of the dose. The oxidation of Hg 0 to Hg 2+ in the red cells is important in limiting the availability of Hg 0 to certain tissues. Thus, after a short residence time in blood (0.6 s after jugular vein injection), 12.9–17% is exhaled in the first pass as compared to 10.4–12.2% with a longer residence time (1.8 s after tail vein injection). Furthermore, there was a general tendency, even at 60 s after dosing, for certain tissues — lung, brain, and heart — to have higher values after dosing from the jugular vein. It was estimated that the half-time for oxidation was 3.3 s. Our results confirm previous observations that the form of inorganic mercury greatly influences the short-term deposition in certain tissues. Thus as compared to Hg 2+, administration of Hg 0 increases lung levels 5–10-fold; brain, 4-fold; and heart, 3-fold. Blood levels are lower after Hg 0, particularly after the higher dose. Such findings are consistent with a model wherein Hg 0 is in part oxidised by red blood cells, the remainder rapidly diffusing in tissues where it is also oxidized to Hg 2+.

Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.

The rapid clearance of circulating liposomes from the bloodstream, coupled with their high uptake by liver and spleen, has thus far been an obstacle to any attempts at targeting to tumors. We have assessed the impact of liposome composition on their clearance from the circulation in normal and tumor-bearing mice and on their uptake by tumors and various normal tissues. By selective changes in lipid composition, while maintaining a mean particle diameter of approximately equal to 100 nm, we have achieved up to a 60-fold increase in the fraction of recovered dose present in blood 24 hr after i.v. injection. Concomitantly, there was a decrease by a factor of 4 of the recovered dose localizing in the liver and spleen, the major organs of the reticuloendothelial system. Parallel experiments in tumor-bearing mice demonstrated a 25-fold increase of the liposome concentration in the tumor when formulations with long and short blood residence time were compared. The most favorable results were obtained with liposomes containing a small molar fraction of a negatively charged glycolipid, such as monosialoganglioside or phosphatidylinositol, and a solid-phase neutral phospholipid as the bulk component. The bio-distribution of such formulations is of considerable therapeutic potential in cancer for increasing the concentration of cytotoxic agents in tumors while minimizing the likelihood of toxicity to the reticuloendothelial system.

Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.

1. Plasma and whole blood concentrations of proguanil and its two major metabolites cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) were measured by a sensitive h.p.l.c. technique in nine healthy adult male volunteers after a single oral dose of proguanil 200 mg. 2. Proguanil was absorbed with a median time to peak plasma concentration of 3 h (range 2-4 h). 3. Peak plasma concentrations of proguanil ranged between 150 and 220 (median 170) ng ml-1 compared with 12 to 69 (median 41) ng ml-1 for the active antimalarial metabolite CG, and 3 to 16 (median 11) ng ml-1 for CPB. Peak (mean +/- s.d.) plasma CG concentrations occurred 5.3 +/- 0.9 h and peak CPB concentrations occurred 6.3 +/- 1.4 h after oral administration of proguanil. 4. Whole blood concentrations of proguanil were approximately five times higher, and whole blood CPB concentrations were four times higher than corresponding plasma values, whereas plasma and whole blood concentrations of CG were similar. 5. A triexponential function was fitted to these data; mean (+/- s.d.) values for the AUC were 3046 +/- 313 ng ml-1 h for proguanil, 679 +/- 372 ng ml-1 h for CG and 257 +/- 155 ng ml-1 h for CPB. 6. Plasma and whole blood concentrations of proguanil and its metabolites declined in parallel with terminal elimination half-lives estimated as 16.1 +/- 2.9 h and 15.7 +/- 2.4 h, respectively. Mean residence times in plasma and whole blood were estimated as 21.2 +/- 4.9 and 19.3 +/- 2.4 h.

Low‐stress hemolysis in laminar blood flow: Bulk and surface effects in capillaries

AbstractHuman blood (blood bank, expired) sheared through stainless steel capillary tubing (508 μm ID) is analyzed for plasma hemoglobin to study the effect of shear‐induced blood damage within the low‐stress regime (stress ≤ 20 Pa). Blood damage results are described in terms of capillary length (related to blood residence time) and wall shear rate for assessing bulk and surface effects. A phenomenological model is proposed to explain these experimental results, obtained over a shear rate range to 7,000 s−1.

Prediction of Minimal Ventilation Requirements for Oxygenation in a Bubble and Membrane Blood Oxygenator During Cardiopulmonary Bypass

2300 Optiflo II and 80 Sci-Med blood oxygenator cardiopulmonary operative records were studied to define the semilogarithmic relationship between the PaO2 and the gas-to-blood flow ratio or the percent FIO2 respectively. A mathematical model was developed to consider the linear effects of oxygenator blood residence time, temperature, hematocrit and the continuously monitored venous inlet % O2 saturation of hemoglobin on the slope and Y -intercept of the device semilog PaO2 function curve. The ventilation of five Optiflo II patient circuits (37 blood gas determinations) and five Sci-Med patient circuits (40 blood gases) ventilation was controlled by intrabypass evaluation of a mathematical statement as each of the four continuously monitored independent variables were altered. The formulae were solved to generate gas-to-blood flow ratios and FIO2’s to yield PaO2’s of 150 mmHg. The average resulting PaO2 in the Optiflo II group = 158 ± 55 mmHg (mean ± 1 S.D.), the PaO2 falling within 150 ± 60 mmHg 70.3% of the time. The average resulting PaO2 in the Sci-Med group = 180 ± 59 mmHg, the PaO2 falling within 150 ± 60 mmHg 67.5% of the time. The minimal ventilation requirements to achieve blood oxygenation were quantitated, formulated, and tested with success.

Theory of CO2 Exchange in Trout Gills*

ABSTRACT A computer simulation of countercurrent CO2 exchange in fish gills was constructed to examine effects of variations in blood and water flow rates. CO2 output was sensitive to both blood and water flow rates, contrary to experimental data. Various explanations of the contradiction are discussed, including patterns of gill perfusion and possible shunting of blood. A simplified version of the model was also used to demonstrate extreme sensitivity of COS efflux to variations of the residence time of blood in the gills. Data from the literature on reaction rate constants for the CO2/carbonate/ bicarbonate system are summarized, and the importance of some of these reactions is examined.

An assessment of the expression C=Q(1-exp (-PS/Q)) for estimating capillary permeabilities

A critical analysis is made of the above expression for estimating capillary permeabilities from data for the transient exchange of inert substances with blood. It is concluded that the equation is based upon an extrapolation of steady-state conditions which introduces large errors, unless used over the residence time of blood in a capillary. The use of PS as a general index of tissue permeability to be compared with Q in assessing the factors controlling blood-tissue exchange is shown to be potentially misleading.