Determination of Gallium Concentration in “Blood-Free” Tissues Using a Radiolabeled Blood Marker

Triplett, J. W.; Hayden, T. L.; McWhorter, Lisa K.; Gautam, Sushen R.; Kim, E.E.; Bourne, David W. A.

doi:10.1002/jps.2600740922

Cited by 19 publications

(17 citation statements)

References 16 publications

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“…The intravascular equilibrium of albumin is reached so rapidly that 90% of intravascular equilibrium is achieved within the first 2 min. The results of this study clearly show that in the dog the volume of blood trapped per tissue weight unit is particularly high in the liver, particularly low in the brain and muscle, confirming previous data in the rat and the guinea-pig [1,2,4], the heart being in an intermediate position. Usually less than 10% of the injected material passes out of the vascular pool during the first 2 h [5].…”

Section: Discussionsupporting

confidence: 90%

“…The rate of this exchange process is dependent upon the porosity of the vascular membrane and varies from tissue to tissue [4]. Indeed, when introduced into the vascular system, radioiodinated albumin undergoes rapid intravascular dilution followed by slower exchange between vascular and extravascular fluids.…”

Section: Discussionmentioning

confidence: 99%

“…Assuming that all the radioactive albumin injected remained in the blood compartment, which nevertheless remains an approximation [4], the volume of blood trapped in each tissue (V t , mL/g) was calculated from the radioactivity measured in blood as well as in the tissues according to the formula V t ¼ R t · V/R i , where R t is the tissue radioactivity (c.p.m./g).…”

Section: E T H O D Smentioning

confidence: 99%

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Is it important to correct apparent drug tissue concentrations for blood contamination in the dog?

Giudicelli¹,

Dricot²,

Moati³

et al. 2004

Fundamemntal Clinical Pharma

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The goal of this study was to quantify in the dog the error that is made in assessing drug tissue concentrations when no correction for blood contamination is performed and hence to determine in which organs such a correction should be made. The organs investigated were the heart, the brain, the liver and the skeletal muscle, and the test drug used was the H1-antihistamine, cetirizine (0.1 or 0.6 mg/kg/day for 3 days, orally, n = 6 dogs). Radiolabelled serum albumin was used to quantitate blood trapped in the tissues. Blood and tissue samplings were performed 2 h after the last drug administration. Mean (+/-SEM) volumes of blood trapped in the liver, heart, muscle and brain were 263 +/- 12, 91 +/- 3, 27 +/- 1 and 20 +/- 2 microL/g, respectively. Apparent tissue/blood concentration ratios of cetirizine were 2.39 +/- 0.33, 1.11 +/- 0.09, 0.77 +/- 0.07 and 0.37 +/- 0.05 in the four organs. When correction for residual blood is not performed, cetirizine concentrations are underestimated (-13.6 +/- 3.2%) in the liver, slightly overestimated (+4.7 +/- 1.5 to +6.3 +/- 2.8%) in the brain, and neither over nor underestimated in the heart and muscle. Simulation data over a wide range of theoretical drug tissue/blood concentration ratios indicate that in the dog: (a) for the liver, correction of apparent tissue concentration for residual blood should be performed when the drug tissue/blood concentration ratio achieved is <0.8 or >4, (b) for the heart, correction should be made when this ratio is < or =0.4 and (c) for the brain and muscle, no correction is necessary unless the ratio is < or =0.1.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: E T H O D Smentioning

confidence: 99%

See 1 more Smart Citation

Is it important to correct apparent drug tissue concentrations for blood contamination in the dog?

Giudicelli¹,

Dricot²,

Moati³

et al. 2004

Fundamemntal Clinical Pharma

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“…The brain nicotine content was corrected for the contribution of blood nicotine in brain [29,30], using a volume fraction of 1.9% blood in brain [31]. …”

Section: Methodsmentioning

confidence: 99%

Increased efficacy of a trivalent nicotine vaccine compared to a dose-matched monovalent vaccine when formulated with alum

Villiers

Cornish

Troska

et al. 2013

Vaccine

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Vaccination against nicotine is a potential treatment for tobacco smoking. Clinical trials show effect only in high antibody responders; therefore it is necessary to increase the effectiveness of nicotine vaccines. The use of a multivalent vaccine that activates several B cell populations is a possible approach to increase antibody response. The aim of this study was to investigate whether three different nicotine immunogens could be mixed to generate independent responses resulting in additive antibody titers, and whether this would alter nicotine distribution to a greater extent than antibodies generated by a monovalent vaccine. When immunogens were administered s.c. with alum adjuvant, the trivalent vaccine generated significantly higher titers and prevented the distribution of an i.v. nicotine dose to brain to a greater extent than an equivalent dose of a monovalent vaccine. The number of rats with antibody titers >1:10,000 was significantly increased in the trivalent group compared to the monovalent group. There were no correlations between the titers generated by the different nicotine immunogens in the trivalent vaccine, supporting the hypothesis that the immunogens generated independent responses from distinct populations of B cells. In contrast, when administered i.p. in Freund’s adjuvant, the trivalent nicotine vaccine was not more immunogenic than its component monovalent vaccine. Vaccine immunogenicity was suppressed if unconjugated protein was added to the monovalent vaccine formulated in Freund’s adjuvant, compared to monovalent vaccine alone. These data suggest a protein–protein interaction that affects titers negatively and is apparent when the vaccines are formulated with Freund’s adjuvant. In summary, a trivalent nicotine vaccine formulated with alum showed significantly higher efficacy than a dose-matched monovalent vaccine and may offer a strategy for increasing nicotine vaccine immunogenicity. This approach may be generalizable to other nicotine immunogens or vaccines for other addictive drugs.

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“…Total liver protein concentration showed no difference between the two strains (225 vs. 230 mg/g liver; P ϭ 0.348), consistent with the data from untreated animals ( Table 1). Because blood retention is ϳ25% in the total wet liver (14,34), the plasma contribution to liver weight would be ϳ14%, because the hematocrit of the mouse is typically ϳ45% (9). Therefore, the plasma protein contribution, ϳ7 mg/g liver, which accounts for Ͻ3% of total liver protein, was insignificant.…”

Section: Plasma [ 3 H]albumin and [ 3 H]transferrin After [ 3 H]leucimentioning

confidence: 99%

Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces

Kim¹,

Bronson²,

Hayton³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

132

107

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It is now understood that the nonclassical major histocompatibility complex-I molecule FcRn binds albumin and retrieves it from an intracellular degradative fate. Whether FcRn in the liver modulates albumin turnover through effects on biosynthesis and production is not known. Thus we quantified the appearance of biosynthetically labeled albumin in plasma after an intravenous bolus injection of [ 3 H]leucine in FcRndeficient mice. The production rates for both albumin (FcRn substrate) and transferrin (nonsubstrate) are increased by ϳ20% in FcRndeficient mice compared with normal mice, likely compensating for the lowered plasma oncotic pressure caused by hypoalbuminemia in FcRn-deficient mice. Determining the magnitude of FcRn-mediated effects on albumin turnover, we then measured the steady-state plasma concentrations of biosynthetically labeled albumin and transferrin during [ 3 H]leucine infusion. The concentration of albumin was ϳ40% lower in FcRn-deficient mice compared with normal mice. Furthermore, the ϳ40% lower plasma albumin concentration in FcRndeficient mice along with the ϳ20% increase in albumin production indicate, by the mass-balance equation, that albumin degradation in FcRn-deficient mice is twice that of normal mice. These studies of biosynthetically labeled, and thus native, albumin support our previous finding that FcRn protects albumin from degradation. Permitting quantification of the magnitude of FcRn-mediated recycling, they further indicate that FcRn has extraordinary capacity: the amount of albumin saved from degradation by FcRn-mediated recycling is the same as that produced by the liver. production; clearance; steady-state; kinetics; Fc receptor ALBUMIN and IGG, the two most abundant proteins in plasma, bind at low pH with high affinity to independent sites on the major histocompatibility complex-related Fc receptor (FcRn). Situated in acidic endosomes of virtually all nucleated cells, FcRn binds both ligands after they have been constitutively endocytosed, shunting them back to the pH-neutral cell surface for continuing circulation, thereby rescuing them from their usual lysosomal degradation fate. FcRn-deficient mice that lack such an FcRn-mediated recycling process (13) show shorter half-lives and lower steady-state plasma concentrations (Css) of both proteins than do normal mice (8).From our earlier measurements of radioiodinated albumin clearance (CL) and endogenous Css, we had inferred that the production rate (Rp) of albumin, using the mass-balance equation (Rp ϭ CL ϫ Css), was lower in the FcRn knockout (KO) strain compared with the wild-type (WT) strain (8). However, we acknowledged the estimations of CL for radioiodinated albumin to be only qualitative, for such measurements for albumin have historically been fraught with imprecision due to structural and/or functional alterations induced by purification and iodination (32). In fact, we had anticipated finding a greater albumin Rp in KO mice, for it had long been known that hypoalbuminemia induces an upregulation of the synth...

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Determination of Gallium Concentration in “Blood-Free” Tissues Using a Radiolabeled Blood Marker

Cited by 19 publications

References 16 publications

Is it important to correct apparent drug tissue concentrations for blood contamination in the dog?

Is it important to correct apparent drug tissue concentrations for blood contamination in the dog?

Increased efficacy of a trivalent nicotine vaccine compared to a dose-matched monovalent vaccine when formulated with alum

Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces

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