Transport of protein-bound steroid hormones into liver in vivo.

Pardridge, William M.; Mietus, Lawrence J.

doi:10.1152/ajpendo.1979.237.4.e367

Cited by 59 publications

(44 citation statements)

References 16 publications

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“…There is an increasing body of evidence indicating that CBG-bound corticosteroids are available for transport into rat liver (29)(30)(31)(32) and peripheral tissues such as rabbit brain (33). Pardridge (34) suggests that in the rat there are microcirculatory mechanisms that catalyze the enhanced dissociation of corticosterone from CBG.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Circulating Corticosterone in Infant Rats

1988

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ABSTRACT. Corticosterone plays an important role in the regulation of postnatal development in the rat. Basal concentrations of plasma corticosterone increase markedly during the 3rd wk of life. To date, however, the physiologic bases of this increase have remained unclear. To understand the determinants of circulating concentrations of corticosterone during this period, the plasma half-life of disappearance at steady state (tlh), the apparent volume of distribution, and metabolic clearance rate were determined after injection of a tracer dose of 3H-corticosterone in rats at 12, 16, and 22 days of age. The tlh for total plasma corticosterone decreased with increasing age. The volume of distribution decreased even more steeply and, consequently, the MCR displayed a highly significant decline between 12 and 22 days of age. As plasma concentrations of corticosteroid-binding globulin are known to increase markedly during this period, the t~ of protein-bound corticosterone was measured and that of free corticosterone was computed. At all ages the tth of bound corticosterone was less than that of free corticosterone. Protein binding of the injected 3H-corticosterone increased significantly with development. Thus, increased binding of corticosterone is associated with decreased t~. The increasing association of corticosterone with corticosteroid-binding globulin during this developmental period is the most likely explanation for the steep decline of volume of distribution and thus of the metabolic clearance rate for corticosterone. The latter provides, for the first time, an understanding of the basis of the developmental increase in plasma concentrations of corticosterone. (Pediatr Res 24: 595-599,1988)

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Section: Discussionmentioning

confidence: 99%

Kinetics of Circulating Corticosterone in Infant Rats

1988

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“…However, the validity of this free-drug (hormone) hypothesis has been challenged by recent experimental observations on the transport of certain highly bound ligands. For example, the hepatic uptake of a number of organic anions (1)(2)(3)(4)(5), steroids (6,7), thyroxine (8,9), and drugs (10) is greater than predicted by their in vitro binding characteristics, and the rate of transport correlates better with the albumin-bound concentration than the unbound level. The brain extraction of drugs such as valproic acid (1 1) and benzodiazepines (12) as well as steroids (7,(13)(14)(15) and thyroid hormones (7) has also been interpreted to indicate a role for albumin in transmembrane transport beyond that associated with the simple binding interaction.…”

Section: Introductionmentioning

confidence: 99%

Plasma binding and transport of diazepam across the blood-brain barrier. No evidence for in vivo enhanced dissociation.

Dubey¹,

McAllister²,

Inoue³

et al. 1989

J. Clin. Invest.

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The tissue uptake of extensively plasma-bound compounds is reportedly inconsistent with the conventional free-drug hypothesis limiting transport to unbound moiety in rapid intracapillary equilibrium with bound complex. Instead, proteinmediated/cell surface enhancement of dissociation has been postulated to occur in the microvasculature. This possibility was investigated by studying the passive transport of diazepam across the blood-brain barrier. Microdialysis probes placed within the vena cava and brain cortex were used to directly compare steady-state, interstitial unbound diazepam levels in both Wistar and genetically analbuminemic rats. The absence of albumin in the latter increased the unbound fraction of diazepam by almost fivefold; however, in both groups, the ratio of unbound concentrations in brain and blood at equilibrium was equal to unity. If enhanced dissociation occurred in the microvasculature, then the unbound brain level should have been greater than that in the systemic circulation. It is probable that earlier findings suggestive of protein-mediated transport reflect a nonequilibrium phenomenon. Comparison of the extent of diazepam's in vivo binding in blood by microdialysis to that estimated in vitro using conventional equilibrium dialysis with microcells showed good agreement, thus validating a widely accepted assumption of equivalency of these two values.

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“…Conversely, the rate of estradiol or cortisol dissociation from sex hormone binding globulin or corticosteroid binding globulin, respectively, is relatively fast (4,5) compared with the long transit time in liver, 5-10 s (6). Moreover, both albumin-bound and globulin-bound estradiol or cortisol are available for transport into liver (7).…”

Section: Introductionmentioning

confidence: 99%

“…At 18 s after injection, a time sufficient for a single circulatory pass of the bolus through liver (12), the portal vein was transected and the right major lobe of liver was immediately removed. The liver tissue and the injection solution were prepared for double isotope 3H, 1251 liquid scintillation counting as described previously (7,10). The liver uptake index (LUI) was calculated as LUI(%) = (1251/3H) disintegrations per minute (liver)/(125I/3H) disintegrations per minute (injection solution) x 100.…”

Section: Introductionmentioning

confidence: 99%

“…The LUI = ET/ER where ET and ER are the percent extraction of the test and reference isotopes, respectively, at 18 s after rapid portal injection. Because ER is known under these experimental conditions (ER = 0.65±0.04, mean+SE, n = 8 rats, [7]), the LUI may be converted to ET. The rate of liver blood flow under the present experimental conditions is 1.4 ml/min per g (7); assuming a hematocrit of 40%, the rate of plasma flow is -2.3 ml/min per g. Given the rate of plasma flow (F), the ET may be converted to unidirectional clearance (Cl), i.e., Cl = ETF.…”

Section: Introductionmentioning

confidence: 99%

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Influx of Thyroid Hormones into Rat Liver In Vivo

Pardridge¹,

Mietus²

1980

J. Clin. Invest.

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A B S T R A C T The transport of ['25I]thyroxine (T4) and [1-5I]triiodothyronine (T3) into liver was investigated with a tissue sampling-portal vein injection technique in the anesthetized rat. The method allows the investigation of the effects of plasma proteins in human serum on the unidirectional influx of T4 or T3 into liver cells. The percent extraction of unidirectional clearance of T3 and T4 was 77±+2% and 43+2%, respectively, after portal injection of a bolus of Ringer's solution. Cell membrane transport of T4 or T3 was nonsaturable because 50-,uM concentrations of unlabeled hormone had no effect on transport. The addition of bovine albumin in concentrations of 1, 5, or 10 g/100 ml bound >98% of T4 or T3 in vitTo, but had no significant effect on T3 or T4 transport in vivo. Conversely, 10% rabbit antisera specific for T3 or T4, completely abolished the intracellular distribution of thyroid hormone into liver. In the presence of rat serum, which contains albumin and thyroid hormone binding prealbumin (TBPA), 18 and 81% of total plasma T4 and T3, respectively, were available for transport in vivo. The fraction of hormone available for transport in the presence of normal human serum, which contains albumin, TBPA, and thyroid hormone binding globulin (TBG) was 11% for T4 and 72% for T3. The fraction of hormone transported into liver after injection of serum obtained from pregnant or birth control pilltreated volunteers was 4% for T4 (but this was not significantly different from zero) and 54% for T3.These data suggest: (a) The mechanism by which T4 and T3 traverse the liver cell membrane is probably free diffusion. (b) Albumin-bound T4 or T3 iS freely cleared by liver, -50% ofTBG-bound T3 is transported, but little, if any, ofTBPA-bound T4 or TBG-bound T4 iS Dr. Pardridge was the recipient of Clinical Investigator Award AM-00409. Address reprint requests to Dr. Pardridge.

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Transport of protein-bound steroid hormones into liver in vivo.

Cited by 59 publications

References 16 publications

Kinetics of Circulating Corticosterone in Infant Rats

Kinetics of Circulating Corticosterone in Infant Rats

Plasma binding and transport of diazepam across the blood-brain barrier. No evidence for in vivo enhanced dissociation.

Influx of Thyroid Hormones into Rat Liver In Vivo

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