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Targeted Delivery of Hormones to Tissues by Plasma Proteins

William M. Pardridge

10.1002/cphy.cp070114

Source: Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology

Originally published: 1998

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Organ Physiology of Solute Exchange Through Capillary Walls
1.1 Quantitation of Capillary Solute Transport: Kety‐Renkin‐Crone Equation
1.2 Capillary Geometry, Organ Blood Flow, and Capillary Transit Times
1.3 Capillary Membrane Permeability
2 Capillary Physiology of Steroid and Thyroid Hormone Transport
2.1 Plasma Protein–Binding Kinetics
2.2 Dissociation‐Limited Transport
2.3 Enhanced Dissociation Mechanism of Plasma Protein–Mediated Transport
2.4 Transcapillary Transport of Protein–Hormone Complex
2.5 Physiology‐Based Model of Cellular Bioavailable Hormone
2.6 Experimental Attempts to Measure Free Cellular Hormone
3 Molecular Physiology of Hormone‐Binding Plasma Proteins
3.1 Albumin
3.2 Prealbumin (Transthyretin)
3.3 Thyroid Hormone–Binding Globulin
3.4 Corticosteroid‐Binding Globulin
3.5 Sex Hormone–Binding Globulin
3.6 α1‐Acid Glycoprotein (Orosomucoid)
4 Summary
Figure 1. Figure 1.

The role of hormone‐binding plasma proteins in the targeted delivery of hormones to tissues in vivo emerges from a fusion of two otherwise separate disciplines: capillary physiology and protein–ligand mass action–binding equilibria.
Figure 2. Figure 2.

The driving force in nuclear receptor hormone occupancy is the concentration of cellular free (exchangeable) hormone, which is directly proportional to the in vivo capillary bioavailable (exchangeable) hormone. Capillary bioavailable hormone, therefore, is the link between hormonal secretion and hormonal action/receptor occupancy. Although in vitro measurements of free hormone in blood reflect the concentration of free hormone in systemic (arterial or venous) circulation, in vivo methods must be employed to estimate the capillary bioavailable hormone. [From Pardridge 170 with permission.]
Figure 3. Figure 3.

The nuclear receptor dissociation constant (KD) for estradiol or testosterone approximates the concentration of albumin‐bound estradiol or testosterone but is log orders greater than the concentration of free estradiol or testosterone measured in vitro. [From Pardridge 170 with permission.]
Figure 4. Figure 4.

Delivery of hormones to tissues in vivo from the circulating plasma protein–bound pool may be viewed within the context of three distinct models: the dissociation‐limited model, the enhanced dissociation model, and the model of receptor‐mediated uptake of hormone–plasma protein complex. If the latter two models are operative, then the cellular free hormone is predicted by in vitro measurements of plasma protein–bound hormone. Conversely, when the dissociation‐limited model is operative, free cellular hormone is predicted by the free hormone measured in vitro.
Figure 5. Figure 5.

A: Structures of steroid hormones with emphasis on the polar function of groups that form hydrogen bonds with water. The hydrogen bond number (N) is given in parentheses and is equal to the total number of hydrogen bonds formed between solvent water and the individual steroid molecule. B: Brain uptake index of five different [3H]‐labeled steroid hormones is shown as means ± SE (n = 3–5 rats per point). [From Pardridge 168 and Pardridge and Mietus 184 with permission.]
Figure 6. Figure 6.

Unidirectional extraction of [3H]‐testosterone by rat brain is plotted vs. the concentration of bovine albumin present in carotid arterial injection solution. Experimentally observed extraction values are represented by closed circles (mean ± SE, n = 3–6 animals per point). Extraction values predicted by fitting the experimental data to the KRC equation are shown by open circles, and curve fitting gives the two parameters k3t (plasma to tissue influx by time) and (in vivo dissociation constant); t = 1/k10. Dashed line represents extraction values predicted by substituting into the KRC equation the albumin concentration, the k3t product, and the in vitro albumin–testosterone dissociation constant, KD = 53 ± 1 μM. Therefore, the dashed curve gives the expected inhibition of testosterone transport caused by hormone binding to albumin if testosterone was not available for transport into brain from the circulating albumin‐bound pool. However, since albumin‐bound testosterone is available via an enhanced dissociation mechanism, the upper curve is observed and the in vivo (2500 ± 700 μM) is much greater than the KD in vitro. [From Pardridge and Landaw 179 with permission.]
Figure 7. Figure 7.

Three‐dimensional structure of albumin as deduced from the primary amino‐acid sequence by Brown 22, 23. Albumin is composed of three domains and six hemicylinders. Ligand‐binding sites are interiors of the six hemicylinders of the albumin molecule. This model illustrates the high flexibility of albumin, and a marked increase in ligand dissociation is expected with a slight uncoiling caused by conformational changes about the binding site. Conformational changes are ligand‐ and tissue‐specific. For example, steroid or thyroid hormone dissociation from albumin is enhanced in brain capillaries, whereas propranolol or lidocaine dissociation is not (Table 5). Conversely, the dissociation of propranolol or lidocaine from albumin is markedly enhanced in the liver microcirculation.
Figure 8. Figure 8.

A: Percent extraction (ET) of inulin and three plasma proteins across the rat prostate gland microvasculature following a single arterial injection. Data are means ± SE (n = 3–7 rats per point). The ET values of albumin, transferrin, and inulin are comparable, whereas there is a marked increase (P < 0.05) of the prostatic extraction of testosterone‐binding globulin (TeBG). B: Darkfield micrograph of thaw‐mount autoradiogram of rat ventral prostate gland obtained 60 s after a descending aortic infusion of [3H]‐testosterone bound to the sex hormone–binding globulin (SHBG) in human pregnancy serum. These studies show rapid exodus of the [3H]‐testosterone–SHBG complex from prostatic microvessels and rapid distribution into the stromal compartment of the prostate gland. Conversely, when [3H]‐testosterone was infused in buffer without SHBG, the steroid molecule uniformly distributed over both the stromal and epithelial compartments. [From Ellison and Pardridge 55 and Sakiyama et al. 225 with permission.]
Figure 9. Figure 9.

A: Photomicrograph of isolated microvessels obtained from 28‐day‐old rabbit brain. These capillaries were used in radioreceptor assays to probe for the presence of plasma protein–specific receptors. B, left: Binding of [3H]‐testosterone‐binding globulin (TeBG) at 37°C to capillaries isolated from either 28‐day‐old (open circles) or adult (triangles) rabbits. Inclusion of 50% 28‐day‐old rabbit serum results in a marked diminution in the uptake of [3H]‐TeBG by capillaries isolated from 28‐day‐old rabbits. B, right: Uptake of [3H]‐albumin by capillaries isolated from 28‐day‐old rabbit brain is plotted vs. incubation time in the absence (closed circles) or presence (open circles) of a 50% dilution of 28‐day‐old rabbit serum. Residual uptake of [14C]‐sucrose, an extracellular fluid marker, is also shown. [From Pardridge et al. 176 with permission.]
Figure 10. Figure 10.

A: Steady‐state model of testosterone transport through the brain capillary wall and into brain cells. Pools of globulin‐bound, albumin‐bound, and free ligand in the systemic circulation are denoted as GL°, AL°, and LF°, respectively; pools of globulin‐bound, albumin‐bound, and plasma bioavailable hormone in the brain capillary are denoted as GL, AL, and LF, respectively. Pools of free and cytoplasmic bound steroid hormone in brain cells are denoted as LM and PL, respectively; t is mean capillary transit time in brain. B: Predicted steady‐state concentrations of testosterone in the various pools of the brain capillary and in brain cells. Pool sizes represent the basal state, which is simulation 1 in Table 9. The concentration of free cytosolic testosterone in brain cells is predicted to approximate the concentration of albumin‐bound hormone in the circulation but is more than tenfold greater than the concentration of free hormone measured in vitro by equilibrium dialysis. [From Pardridge and Landaw 180 with permission.]
Figure 11. Figure 11.

A: Steady‐state model of triiodothyronine transport in the liver microcirculation in vivo. Rate constants and hormone pools are defined in Table 10. B: The parameters in Table 10 were substituted into the steady‐state model equation using a program in BASIC to generate the predicted pool‐size concentrations shown in the figure, which correspond to simulation 1 of Table 11. GL°, AL°, and LF°: pools of globulin‐bound, albumin‐bound, and free ligand, respectively. GL, AL, and LF: pools of globulin‐bound, albumin‐bound, and plasma available hormone, respectively. LM and PL, pools of free and cytoplasmic bound thyroid hormone, respectively. [From Pardridge 173 and Pardridge and Landaw 181 with permission.]
Figure 12. Figure 12.

A: Fractions of free plus albumin‐bound testosterone and estradiol in vitro and bioavailable testosterone and estradiol in rat salivary gland in vivo are compared, showing that sex hormone–binding globulin (SHBG)‐bound estradiol, but not SHBG‐bound testosterone, is readily available for transport into rat salivary gland. In addition, albumin‐bound testosterone or estradiol is bioavailable in salivary gland capillaries. These in vivo measurements were made at 15 s after a single carotid artery injection of [3H]‐hormone mixed in human female serum. This short period is sufficient to allow for rapid distribution of hormone into the glandular epithelium, as shown by the autoradiographic studies in B. [From Pardridge 170 with permission.] B: Thaw‐mount autoradiogram of rat salivary gland removed 15 s after single carotid artery injection of [3H]‐estradiol dissolved in Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin. The [3H]‐estradiol is found throughout the gland, with concentration over the salivary gland ductules. The tissue was counterstained after autoradiography with methylgreen‐pyronin. [From Cefalu et al. 28 with permission.] C: One‐dimensional thinlayer chromatographic separation of brain, cervical lymph node, and salivary gland homogenates of tissue obtained 60 s after a single carotid artery injection of [3H]‐testosterone (50 μCi/ml) in Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin. Migration of testosterone or several other metabolites in the one‐dimensional system is shown. The minor peak in the brain and lymph node studies that co‐migrated with androstenedione (peak 2) represents an impurity in the isotope, as this was found also in the [3H]‐testosterone obtained from the manufacturer. The data show that while testosterone is rapidly metabolized in salivary gland, there is no significant metabolism in the whole brain or lymph node within 60 s after administration in vivo. [From Cefalu et al. 28 with permission.]
Figure 13. Figure 13.

Amino‐acid sequence of bovine serum albumin, displayed in a model showing the linking of cysteines to form multiple loops as proposed by Brown 22.
Figure 14. Figure 14.

Three‐dimensional structure of human serum albumin predicted from X‐ray diffraction studies. The amino (N) and carboxyl (C) termini are shown. The six different putative binding sites on the albumin molecule are shown, designated IA, IB, IIA, IIB, IIIA, and IIIB. The principal drug‐binding sites on albumin are IIA and IIIA. [From Carter and He 26 with permission.]
Figure 15. Figure 15.

Approximate amino‐acid residues comprising the six binding domains in serum albumin. [Drawn from data of Carter and He 26 with permission.]
Figure 16. Figure 16.

Unidirectional extraction of [125I]‐thyroxine (T4) into rat liver in vivo is shown for three types of portal vein injection vehicles: Ringer‐HEPES buffer plus 0.1 g/100 dl bovine albumin, normal human serum, or serum obtained from patients with familial dysalbuminemic hyperthyroxinemia (FDH) in the presence of 0 or 25 μM unlabeled T4, and rabbit anti‐T4 antiserum. Extraction of T4 following portal vein injection of Ringer‐HEPES buffer represents the situation when approximately 100% of T4 is available for extraction by hepatocytes; extraction of T4 by liver following portal vein injection of the isotope dissolved in the T4 antiserum represents the baseline extraction when the amount of injected T4 available for extraction by hepatocytes is essentially nil. Horizontal bars represent the mean ± one standard deviation for the extraction of T4 in either Ringer's solution or the T4 antiserum. [From Cefalu et al. 29 with permission.]
Figure 17. Figure 17.

Stereo view of the three‐dimensional structure predicted from X‐ray diffraction for the prealbumin homotetramer. [From Blake and Oatley 13 with permission.]
Figure 18. Figure 18.

A: Extraction of [125I]‐thryoxine (T4) into rat liver following portal vein injection of the isotope dissolved in three different solutions: Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin (upper horizontal bar), control or thyroid hormone–binding globulin (TBG)–deficient human serum or normal rat serum (closed circles), T4‐specific rabbit antiserum (lower horizontal bar). Extractions obtained following injection of Ringer's solution or T4 antiserum represent the hepatocyte extraction when approximately 100% and 0%, respectively, of labeled hormone is available for transport into liver. Horizontal bars represent mean ± SE (n = 3–6 rats per point). The number of subjects in each category is shown in parentheses. B: Extraction of [125I]‐T4 by rat liver in vivo is plotted vs. the concentration of human prealbumin in the portal vein injection solution. Human prealbumin and [125I]‐T4 were mixed with either 5 or 0.1 g/dl bovine albumin or 5 g/dl dextran (65,000 daltons). Dashed line represents the extraction of T4 predicted on the basis of the bound T4 fraction as measured in vitro by equilibrium dialysis at each concentration of prealbumin. All concentrations of human prealbumin (0.01–0.3 mg/ml) bound more than 96% of T4 in vitro. Solid horizontal line represents hepatic extraction of T4 in the presence of a 10% T4 antiserum. [From Pardridge et al. 188 with permission.]
Figure 19. Figure 19.

Heterogeneity of thyroid hormone–binding globulin (TBG) structure and function Right: Extraction of [125I]‐thyroxine (T4) or [125I]‐triiodethyronine (T3) by rat liver is plotted vs. the type of serum added to the portal vein injection solution. Plasma‐free solutions contain 0.1 g/dl bovine albumin; T4‐, or T4‐specific antiserum solutions were diluted to 10%. All other samples were injected at 67% serum solutions. Each point represents a different patient, volunteer, or animal. Boxes represent the mean ± SD. Normal, human, and cord samples were obtained from both females and males. BCP, birth control pills. Left: Autoradiogram of [125I]‐T3 or [125I]‐T4 bound to TBG isoforms, albumin isoforms, and prealbumin in serum from normal male subjects, cirrhotic male patients, pregnant subjects, and normal female subjects following separation by isoelectric focusing. The pH values of the gel are shown in the ordinate of the figure. [From Pardridge 173 with permission.]
Figure 20. Figure 20.

A: Brain uptake index (BUI) for [3H]‐testosterone and [3H]‐estradiol relative to [14C]‐butanol is shown for five to nine patients in seven clinical conditions. Vertical rectangles are means ± SD; horizontal line is mean of testosterone or estradiol BUI in absence of plasma proteins. BCP, birth control pill–treated women; PMP, postmenopausal women. B: Reciprocal of BUI for [3H]‐testosterone (T) and [3H]‐estradiol (E2) is plotted vs. the level of sex hormone–binding globulin (SHBG) in human serum. Data for BUI are shown in A. P, pregnancy; B, birth control pills; T, thin postmenopausal female; F, normal follicular phase female; O, obese postmenopausal female; M, normal male; H, hirsute female. Data obtained by linear regression are shown in inset for both plots. [From Pardridge et al. 186 with permission.]
Figure 21. Figure 21.

In vitro free plus albumin‐bound, in vivo brain bioavailable, and in vivo liver bioavailable fractions for human male serum for three steroid hormones. [From Pardridge 171 with permission.]
Figure 22. Figure 22.

Metabolic clearance rate (MCR) and transport clearance rate (TCR) ratios for testosterone (T)/dihydrotestosterone (DHT) are compared for humans and rabbits. Human TCR ratio was measured in rat brain using human male serum. Rabbit TCR ratio was measured in rabbit uterus using rabbit serum 1. Human and rabbit MCR ratios were reported by Vermeulen and Andó 270 and Mahoudeau et al. 140, respectively. The T/DHT MCR ratio in the rhesus monkey 231 is virtually identical to the ratio for humans 270.
Figure 23. Figure 23.

A: Rat brain extraction of [3H]‐testosterone or [3H]‐estradiol after carotid arterial injection of labeled hormone mixed in either male cirrhotic or control human male serum. Rectangles represent means ± SD. The data show that unidirectional testosterone extraction by brain is decreased 33% (P < 0.0025) using cirrhotic serum, and this parallels a 2.6‐fold increase in sex hormon–binding globulin (SHBG) and a 40% decrease in serum albumin in cirrhosis. However, unidirectional clearance of estradiol by rat brain was not decreased using cirrhotic serum, despite the marked increase in SHBG, the decrease in albumin, and the 41% decrease in the non‐SHBG‐bound fraction of estradiol in cirrhosis. Brain bioavailable estradiol using cirrhotic serum, 54 ± 4%, exceeds non‐SHBG‐bound estradiol, 36 ± 6%, in cirrhotic serum, indicating that SHBG‐bound estradiol is available for transport into brain from plasma protein–bound pools in cirrhotic serum. Conversely, SHBG‐bound estradiol was not available for transport into brain when serum was obtained from other clinical groups (Fig. 20). [From Sakiyama et al. 224 with permission.]

B: Isoelectric focusing separation of [3H]‐testosterone‐and [3H]‐estradiol‐binding isoforms of SHBG in concanavalin‐A–glycoprotein fraction of a cirrhotic male serum pool and a normal male serum pool. The pH values of the gel are shown by a diagonal line in the bottom half of the figure. C: Profiles of estradiol‐ or testosterone‐binding isoforms of SHBG from B are replotted to allow direct comparison of results between normal male and cirrhotic male serum pools. The pH profile is shown by the diagonal line. [From Terasaki et al. 253 with permission.]
Figure 24. Figure 24.

A: Rat brain extraction of [3H]‐testosterone or [3H]‐estradiol after carotid arterial injection of labeled hormone mixed in either male cirrhotic or control human male serum. Rectangles represent means ± SD. The data show that unidirectional testosterone extraction by brain is decreased 33% (P < 0.0025) using cirrhotic serum, and this parallels a 2.6‐fold increase in sex hormon–binding globulin (SHBG) and a 40% decrease in serum albumin in cirrhosis. However, unidirectional clearance of estradiol by rat brain was not decreased using cirrhotic serum, despite the marked increase in SHBG, the decrease in albumin, and the 41% decrease in the non‐SHBG‐bound fraction of estradiol in cirrhosis. Brain bioavailable estradiol using cirrhotic serum, 54 ± 4%, exceeds non‐SHBG‐bound estradiol, 36 ± 6%, in cirrhotic serum, indicating that SHBG‐bound estradiol is available for transport into brain from plasma protein–bound pools in cirrhotic serum. Conversely, SHBG‐bound estradiol was not available for transport into brain when serum was obtained from other clinical groups (Fig. 20). [From Sakiyama et al. 224 with permission.]

B: Isoelectric focusing separation of [3H]‐testosterone‐and [3H]‐estradiol‐binding isoforms of SHBG in concanavalin‐A–glycoprotein fraction of a cirrhotic male serum pool and a normal male serum pool. The pH values of the gel are shown by a diagonal line in the bottom half of the figure. C: Profiles of estradiol‐ or testosterone‐binding isoforms of SHBG from B are replotted to allow direct comparison of results between normal male and cirrhotic male serum pools. The pH profile is shown by the diagonal line. [From Terasaki et al. 253 with permission.]


Figure 1.

The role of hormone‐binding plasma proteins in the targeted delivery of hormones to tissues in vivo emerges from a fusion of two otherwise separate disciplines: capillary physiology and protein–ligand mass action–binding equilibria.



Figure 2.

The driving force in nuclear receptor hormone occupancy is the concentration of cellular free (exchangeable) hormone, which is directly proportional to the in vivo capillary bioavailable (exchangeable) hormone. Capillary bioavailable hormone, therefore, is the link between hormonal secretion and hormonal action/receptor occupancy. Although in vitro measurements of free hormone in blood reflect the concentration of free hormone in systemic (arterial or venous) circulation, in vivo methods must be employed to estimate the capillary bioavailable hormone. [From Pardridge 170 with permission.]



Figure 3.

The nuclear receptor dissociation constant (KD) for estradiol or testosterone approximates the concentration of albumin‐bound estradiol or testosterone but is log orders greater than the concentration of free estradiol or testosterone measured in vitro. [From Pardridge 170 with permission.]



Figure 4.

Delivery of hormones to tissues in vivo from the circulating plasma protein–bound pool may be viewed within the context of three distinct models: the dissociation‐limited model, the enhanced dissociation model, and the model of receptor‐mediated uptake of hormone–plasma protein complex. If the latter two models are operative, then the cellular free hormone is predicted by in vitro measurements of plasma protein–bound hormone. Conversely, when the dissociation‐limited model is operative, free cellular hormone is predicted by the free hormone measured in vitro.



Figure 5.

A: Structures of steroid hormones with emphasis on the polar function of groups that form hydrogen bonds with water. The hydrogen bond number (N) is given in parentheses and is equal to the total number of hydrogen bonds formed between solvent water and the individual steroid molecule. B: Brain uptake index of five different [3H]‐labeled steroid hormones is shown as means ± SE (n = 3–5 rats per point). [From Pardridge 168 and Pardridge and Mietus 184 with permission.]



Figure 6.

Unidirectional extraction of [3H]‐testosterone by rat brain is plotted vs. the concentration of bovine albumin present in carotid arterial injection solution. Experimentally observed extraction values are represented by closed circles (mean ± SE, n = 3–6 animals per point). Extraction values predicted by fitting the experimental data to the KRC equation are shown by open circles, and curve fitting gives the two parameters k3t (plasma to tissue influx by time) and (in vivo dissociation constant); t = 1/k10. Dashed line represents extraction values predicted by substituting into the KRC equation the albumin concentration, the k3t product, and the in vitro albumin–testosterone dissociation constant, KD = 53 ± 1 μM. Therefore, the dashed curve gives the expected inhibition of testosterone transport caused by hormone binding to albumin if testosterone was not available for transport into brain from the circulating albumin‐bound pool. However, since albumin‐bound testosterone is available via an enhanced dissociation mechanism, the upper curve is observed and the in vivo (2500 ± 700 μM) is much greater than the KD in vitro. [From Pardridge and Landaw 179 with permission.]



Figure 7.

Three‐dimensional structure of albumin as deduced from the primary amino‐acid sequence by Brown 22, 23. Albumin is composed of three domains and six hemicylinders. Ligand‐binding sites are interiors of the six hemicylinders of the albumin molecule. This model illustrates the high flexibility of albumin, and a marked increase in ligand dissociation is expected with a slight uncoiling caused by conformational changes about the binding site. Conformational changes are ligand‐ and tissue‐specific. For example, steroid or thyroid hormone dissociation from albumin is enhanced in brain capillaries, whereas propranolol or lidocaine dissociation is not (Table 5). Conversely, the dissociation of propranolol or lidocaine from albumin is markedly enhanced in the liver microcirculation.



Figure 8.

A: Percent extraction (ET) of inulin and three plasma proteins across the rat prostate gland microvasculature following a single arterial injection. Data are means ± SE (n = 3–7 rats per point). The ET values of albumin, transferrin, and inulin are comparable, whereas there is a marked increase (P < 0.05) of the prostatic extraction of testosterone‐binding globulin (TeBG). B: Darkfield micrograph of thaw‐mount autoradiogram of rat ventral prostate gland obtained 60 s after a descending aortic infusion of [3H]‐testosterone bound to the sex hormone–binding globulin (SHBG) in human pregnancy serum. These studies show rapid exodus of the [3H]‐testosterone–SHBG complex from prostatic microvessels and rapid distribution into the stromal compartment of the prostate gland. Conversely, when [3H]‐testosterone was infused in buffer without SHBG, the steroid molecule uniformly distributed over both the stromal and epithelial compartments. [From Ellison and Pardridge 55 and Sakiyama et al. 225 with permission.]



Figure 9.

A: Photomicrograph of isolated microvessels obtained from 28‐day‐old rabbit brain. These capillaries were used in radioreceptor assays to probe for the presence of plasma protein–specific receptors. B, left: Binding of [3H]‐testosterone‐binding globulin (TeBG) at 37°C to capillaries isolated from either 28‐day‐old (open circles) or adult (triangles) rabbits. Inclusion of 50% 28‐day‐old rabbit serum results in a marked diminution in the uptake of [3H]‐TeBG by capillaries isolated from 28‐day‐old rabbits. B, right: Uptake of [3H]‐albumin by capillaries isolated from 28‐day‐old rabbit brain is plotted vs. incubation time in the absence (closed circles) or presence (open circles) of a 50% dilution of 28‐day‐old rabbit serum. Residual uptake of [14C]‐sucrose, an extracellular fluid marker, is also shown. [From Pardridge et al. 176 with permission.]



Figure 10.

A: Steady‐state model of testosterone transport through the brain capillary wall and into brain cells. Pools of globulin‐bound, albumin‐bound, and free ligand in the systemic circulation are denoted as GL°, AL°, and LF°, respectively; pools of globulin‐bound, albumin‐bound, and plasma bioavailable hormone in the brain capillary are denoted as GL, AL, and LF, respectively. Pools of free and cytoplasmic bound steroid hormone in brain cells are denoted as LM and PL, respectively; t is mean capillary transit time in brain. B: Predicted steady‐state concentrations of testosterone in the various pools of the brain capillary and in brain cells. Pool sizes represent the basal state, which is simulation 1 in Table 9. The concentration of free cytosolic testosterone in brain cells is predicted to approximate the concentration of albumin‐bound hormone in the circulation but is more than tenfold greater than the concentration of free hormone measured in vitro by equilibrium dialysis. [From Pardridge and Landaw 180 with permission.]



Figure 11.

A: Steady‐state model of triiodothyronine transport in the liver microcirculation in vivo. Rate constants and hormone pools are defined in Table 10. B: The parameters in Table 10 were substituted into the steady‐state model equation using a program in BASIC to generate the predicted pool‐size concentrations shown in the figure, which correspond to simulation 1 of Table 11. GL°, AL°, and LF°: pools of globulin‐bound, albumin‐bound, and free ligand, respectively. GL, AL, and LF: pools of globulin‐bound, albumin‐bound, and plasma available hormone, respectively. LM and PL, pools of free and cytoplasmic bound thyroid hormone, respectively. [From Pardridge 173 and Pardridge and Landaw 181 with permission.]



Figure 12.

A: Fractions of free plus albumin‐bound testosterone and estradiol in vitro and bioavailable testosterone and estradiol in rat salivary gland in vivo are compared, showing that sex hormone–binding globulin (SHBG)‐bound estradiol, but not SHBG‐bound testosterone, is readily available for transport into rat salivary gland. In addition, albumin‐bound testosterone or estradiol is bioavailable in salivary gland capillaries. These in vivo measurements were made at 15 s after a single carotid artery injection of [3H]‐hormone mixed in human female serum. This short period is sufficient to allow for rapid distribution of hormone into the glandular epithelium, as shown by the autoradiographic studies in B. [From Pardridge 170 with permission.] B: Thaw‐mount autoradiogram of rat salivary gland removed 15 s after single carotid artery injection of [3H]‐estradiol dissolved in Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin. The [3H]‐estradiol is found throughout the gland, with concentration over the salivary gland ductules. The tissue was counterstained after autoradiography with methylgreen‐pyronin. [From Cefalu et al. 28 with permission.] C: One‐dimensional thinlayer chromatographic separation of brain, cervical lymph node, and salivary gland homogenates of tissue obtained 60 s after a single carotid artery injection of [3H]‐testosterone (50 μCi/ml) in Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin. Migration of testosterone or several other metabolites in the one‐dimensional system is shown. The minor peak in the brain and lymph node studies that co‐migrated with androstenedione (peak 2) represents an impurity in the isotope, as this was found also in the [3H]‐testosterone obtained from the manufacturer. The data show that while testosterone is rapidly metabolized in salivary gland, there is no significant metabolism in the whole brain or lymph node within 60 s after administration in vivo. [From Cefalu et al. 28 with permission.]



Figure 13.

Amino‐acid sequence of bovine serum albumin, displayed in a model showing the linking of cysteines to form multiple loops as proposed by Brown 22.



Figure 14.

Three‐dimensional structure of human serum albumin predicted from X‐ray diffraction studies. The amino (N) and carboxyl (C) termini are shown. The six different putative binding sites on the albumin molecule are shown, designated IA, IB, IIA, IIB, IIIA, and IIIB. The principal drug‐binding sites on albumin are IIA and IIIA. [From Carter and He 26 with permission.]



Figure 15.

Approximate amino‐acid residues comprising the six binding domains in serum albumin. [Drawn from data of Carter and He 26 with permission.]



Figure 16.

Unidirectional extraction of [125I]‐thyroxine (T4) into rat liver in vivo is shown for three types of portal vein injection vehicles: Ringer‐HEPES buffer plus 0.1 g/100 dl bovine albumin, normal human serum, or serum obtained from patients with familial dysalbuminemic hyperthyroxinemia (FDH) in the presence of 0 or 25 μM unlabeled T4, and rabbit anti‐T4 antiserum. Extraction of T4 following portal vein injection of Ringer‐HEPES buffer represents the situation when approximately 100% of T4 is available for extraction by hepatocytes; extraction of T4 by liver following portal vein injection of the isotope dissolved in the T4 antiserum represents the baseline extraction when the amount of injected T4 available for extraction by hepatocytes is essentially nil. Horizontal bars represent the mean ± one standard deviation for the extraction of T4 in either Ringer's solution or the T4 antiserum. [From Cefalu et al. 29 with permission.]



Figure 17.

Stereo view of the three‐dimensional structure predicted from X‐ray diffraction for the prealbumin homotetramer. [From Blake and Oatley 13 with permission.]



Figure 18.

A: Extraction of [125I]‐thryoxine (T4) into rat liver following portal vein injection of the isotope dissolved in three different solutions: Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin (upper horizontal bar), control or thyroid hormone–binding globulin (TBG)–deficient human serum or normal rat serum (closed circles), T4‐specific rabbit antiserum (lower horizontal bar). Extractions obtained following injection of Ringer's solution or T4 antiserum represent the hepatocyte extraction when approximately 100% and 0%, respectively, of labeled hormone is available for transport into liver. Horizontal bars represent mean ± SE (n = 3–6 rats per point). The number of subjects in each category is shown in parentheses. B: Extraction of [125I]‐T4 by rat liver in vivo is plotted vs. the concentration of human prealbumin in the portal vein injection solution. Human prealbumin and [125I]‐T4 were mixed with either 5 or 0.1 g/dl bovine albumin or 5 g/dl dextran (65,000 daltons). Dashed line represents the extraction of T4 predicted on the basis of the bound T4 fraction as measured in vitro by equilibrium dialysis at each concentration of prealbumin. All concentrations of human prealbumin (0.01–0.3 mg/ml) bound more than 96% of T4 in vitro. Solid horizontal line represents hepatic extraction of T4 in the presence of a 10% T4 antiserum. [From Pardridge et al. 188 with permission.]



Figure 19.

Heterogeneity of thyroid hormone–binding globulin (TBG) structure and function Right: Extraction of [125I]‐thyroxine (T4) or [125I]‐triiodethyronine (T3) by rat liver is plotted vs. the type of serum added to the portal vein injection solution. Plasma‐free solutions contain 0.1 g/dl bovine albumin; T4‐, or T4‐specific antiserum solutions were diluted to 10%. All other samples were injected at 67% serum solutions. Each point represents a different patient, volunteer, or animal. Boxes represent the mean ± SD. Normal, human, and cord samples were obtained from both females and males. BCP, birth control pills. Left: Autoradiogram of [125I]‐T3 or [125I]‐T4 bound to TBG isoforms, albumin isoforms, and prealbumin in serum from normal male subjects, cirrhotic male patients, pregnant subjects, and normal female subjects following separation by isoelectric focusing. The pH values of the gel are shown in the ordinate of the figure. [From Pardridge 173 with permission.]



Figure 20.

A: Brain uptake index (BUI) for [3H]‐testosterone and [3H]‐estradiol relative to [14C]‐butanol is shown for five to nine patients in seven clinical conditions. Vertical rectangles are means ± SD; horizontal line is mean of testosterone or estradiol BUI in absence of plasma proteins. BCP, birth control pill–treated women; PMP, postmenopausal women. B: Reciprocal of BUI for [3H]‐testosterone (T) and [3H]‐estradiol (E2) is plotted vs. the level of sex hormone–binding globulin (SHBG) in human serum. Data for BUI are shown in A. P, pregnancy; B, birth control pills; T, thin postmenopausal female; F, normal follicular phase female; O, obese postmenopausal female; M, normal male; H, hirsute female. Data obtained by linear regression are shown in inset for both plots. [From Pardridge et al. 186 with permission.]



Figure 21.

In vitro free plus albumin‐bound, in vivo brain bioavailable, and in vivo liver bioavailable fractions for human male serum for three steroid hormones. [From Pardridge 171 with permission.]



Figure 22.

Metabolic clearance rate (MCR) and transport clearance rate (TCR) ratios for testosterone (T)/dihydrotestosterone (DHT) are compared for humans and rabbits. Human TCR ratio was measured in rat brain using human male serum. Rabbit TCR ratio was measured in rabbit uterus using rabbit serum 1. Human and rabbit MCR ratios were reported by Vermeulen and Andó 270 and Mahoudeau et al. 140, respectively. The T/DHT MCR ratio in the rhesus monkey 231 is virtually identical to the ratio for humans 270.



Figure 23.

A: Rat brain extraction of [3H]‐testosterone or [3H]‐estradiol after carotid arterial injection of labeled hormone mixed in either male cirrhotic or control human male serum. Rectangles represent means ± SD. The data show that unidirectional testosterone extraction by brain is decreased 33% (P < 0.0025) using cirrhotic serum, and this parallels a 2.6‐fold increase in sex hormon–binding globulin (SHBG) and a 40% decrease in serum albumin in cirrhosis. However, unidirectional clearance of estradiol by rat brain was not decreased using cirrhotic serum, despite the marked increase in SHBG, the decrease in albumin, and the 41% decrease in the non‐SHBG‐bound fraction of estradiol in cirrhosis. Brain bioavailable estradiol using cirrhotic serum, 54 ± 4%, exceeds non‐SHBG‐bound estradiol, 36 ± 6%, in cirrhotic serum, indicating that SHBG‐bound estradiol is available for transport into brain from plasma protein–bound pools in cirrhotic serum. Conversely, SHBG‐bound estradiol was not available for transport into brain when serum was obtained from other clinical groups (Fig. 20). [From Sakiyama et al. 224 with permission.]

B: Isoelectric focusing separation of [3H]‐testosterone‐and [3H]‐estradiol‐binding isoforms of SHBG in concanavalin‐A–glycoprotein fraction of a cirrhotic male serum pool and a normal male serum pool. The pH values of the gel are shown by a diagonal line in the bottom half of the figure. C: Profiles of estradiol‐ or testosterone‐binding isoforms of SHBG from B are replotted to allow direct comparison of results between normal male and cirrhotic male serum pools. The pH profile is shown by the diagonal line. [From Terasaki et al. 253 with permission.]



Figure 24.

A: Rat brain extraction of [3H]‐testosterone or [3H]‐estradiol after carotid arterial injection of labeled hormone mixed in either male cirrhotic or control human male serum. Rectangles represent means ± SD. The data show that unidirectional testosterone extraction by brain is decreased 33% (P < 0.0025) using cirrhotic serum, and this parallels a 2.6‐fold increase in sex hormon–binding globulin (SHBG) and a 40% decrease in serum albumin in cirrhosis. However, unidirectional clearance of estradiol by rat brain was not decreased using cirrhotic serum, despite the marked increase in SHBG, the decrease in albumin, and the 41% decrease in the non‐SHBG‐bound fraction of estradiol in cirrhosis. Brain bioavailable estradiol using cirrhotic serum, 54 ± 4%, exceeds non‐SHBG‐bound estradiol, 36 ± 6%, in cirrhotic serum, indicating that SHBG‐bound estradiol is available for transport into brain from plasma protein–bound pools in cirrhotic serum. Conversely, SHBG‐bound estradiol was not available for transport into brain when serum was obtained from other clinical groups (Fig. 20). [From Sakiyama et al. 224 with permission.]

B: Isoelectric focusing separation of [3H]‐testosterone‐and [3H]‐estradiol‐binding isoforms of SHBG in concanavalin‐A–glycoprotein fraction of a cirrhotic male serum pool and a normal male serum pool. The pH values of the gel are shown by a diagonal line in the bottom half of the figure. C: Profiles of estradiol‐ or testosterone‐binding isoforms of SHBG from B are replotted to allow direct comparison of results between normal male and cirrhotic male serum pools. The pH profile is shown by the diagonal line. [From Terasaki et al. 253 with permission.]

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Article Title: Targeted Delivery of Hormones to Tissues by Plasma Proteins
 

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William M. Pardridge. Targeted Delivery of Hormones to Tissues by Plasma Proteins. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 335-382. First published in print 1998. doi: 10.1002/cphy.cp070114