The Experts below are selected from a list of 87 Experts worldwide ranked by ideXlab platform

Jan R. Stockigt - One of the best experts on this subject based on the ideXlab platform.

  • Drug effects on triiodothyronine uptake by rat anterior pituitary cells in vitro
    Experimental and clinical endocrinology & diabetes : official journal German Society of Endocrinology [and] German Diabetes Association, 1996
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    In nonthyroidal illness, numerous drugs such as glucocorticoids, dopamine, Fenclofenac, furosemide and diphenylhydantoin may modify the close inverse-feedback relationship between circulating thyroid hormones and TSH. Such effects could involve altered hypothalamic TRH secretion, a direct effect on TSH production by the thyrotroph, alterations in circulating free thyroid hormone concentrations, or changes in thyroid hormone uptake by the thyrotroph. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, the synthetic flavonoid EMD 21388, and diphenylhydantoin, on [125I]T3 cellular uptake in rat pituitary primary cell cultures. Uptake of [125I]T3 (cell-associated counts of washed cells) was measured at 15 min after the addition of 50 pmol/L [125I]T3 in protein-free medium (37 degrees C, pH 7.4). Uptake of [125I]T3 by pituitary cells was 6.0 +/- 1.7% of total counts (mean +/- SD, n = 18). Unlabeled T3 (10 mumols/L) displaced 92% of total uptake. The IC50 of unlabeled T3 for the displacement of [125I]T3 was 1.2 mumols/L. T4 and rT3 were approximately 10% as effective as T3 itself in inhibiting [125I]T3 uptake, while triac did not affect cellular [125I]T3 uptake. Inhibition of [125I]T3 uptake at drug concentrations of 100 mumols/L was seen with the diuretics, furosemide (9%), bumetanide (14%), piretanide (12%) and ethacrynic acid (76%), the NSAID, meclofenamic acid (35%) and Fenclofenac (52%), EMD 21388 (49%), and the anticonvulsant, diphenylhydantoin (23%). Aspirin, up to 500 mumols/L, had no effect on [125I]T3 uptake. Our results indicate that ethacrynic acid, meclofenamic acid, Fenclofenac, EMD 21388 and diphenylhydantoin affect plasma membrane T3 uptake in the pituitary. This potential influence on TSH release will be contrary to the previously-demonstrated direct inhibitory effect of these drugs on TSH release.

  • Effect of Loop Diuretics and Nonsteroidal Antiinflammatory Drugs on Thyrotropin Release by Rat Anterior Pituitary Cells In Vitro
    Metabolism: clinical and experimental, 1995
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    The close inverse-feedback relationship between serum free thyroxine (T4) and thyrotropin (TSH) is altered in some patients receiving therapeutic doses of drugs such as furosemide, Fenclofenac, and diphenylhydantoin. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, and diphenylhydantoin on TSH release in rat anterior pituitary cells in primary culture. TSH content of the culture medium was measured at 22 hours at 37°C either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) i either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) in medium containing 0.5% bovine serum albumin. The mean basal TSH release by pituitary cells was 6.2 ± 1.2 ng/mL (n = 10) and was not influenced by unlabeled triiodothyronine ([T3] 100 nmol/L) or any of the drugs tested at ≤ 400 μmol/L, except ethyacrynic acid. TRH 10 nmol/L increased mean TSH release by 346% ± 95% (n = 10). T3 1 and 100 nmol/L inhibited TRH-stimulated TSH release by 24% and 31%, respectively (P < .001), whereas TRH-stimulated TSH release was inhibited by 100 μmol/L meclofenamic acid (29%), Fenclofenac (28%), furosemide (24%), and diphenylhydantoin (48%) (P < .001 v TRH alone). Meclofenamic acid and furosemide (100 μmol/L) did not significantly alter the inhibitory effect of T3 1 nmol/L on TRH-stimulated TSH release. These in vitro studies suggest that meclofenamic acid, Fenclofenac, furosemide, and diphenylhydantoin could influence TSH release by attenuating the TSH response to TRH. This effect may influence T4-TSH relationships when these agents are used in vivo.

  • Alterations in hepatocyte uptake and plasma binding of thyroxine in nonthyroidal illness and caloric deprivation
    Trends in endocrinology and metabolism: TEM, 1995
    Co-Authors: Chen-fee Lim, Jan R. Stockigt, Georg Hennemann
    Abstract:

    Low plasma T(3) in severe illness is widely thought to be due principally to inhibition of 5'-deiodinase activity, but other factors also contribute to this response. Abnormal plasma constituents, namely, 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate in uremia, and elevated bilirubin and nonesterified fatty acids (NEFA) can impair T(4) transport into hepatocytes, thereby contributing to the lowering of plasma T(3). Assessment of possible endogenous or exogenous inhibitors of T(4) binding to plasma proteins is prone to dilution-dependent artifacts, which can lead to overestimation or underestimation of competitor potency, depending on experimental details. Because the potency of such competitors is a function of their free concentrations in undiluted serum, inhibitory activity may be enhanced by substances that impair their albumin binding. Oleic acid or CMPF can inhibit the effect of drugs such as furosemide or Fenclofenac.

  • A naturally occurring furan fatty acid enhances drug inhibition of thyroxine binding in serum
    Metabolism: clinical and experimental, 1993
    Co-Authors: Chen-fee Lim, Jan R. Stockigt, Andrea J. Curtis, John W. Barlow, Kenneth N. Wynne, Duncan J. Topliss
    Abstract:

    Abstract We studied the thyroxine (T 4 )-displacing effects of a naturally occurring, highly albumin-bound furanoid acid that accumulates in serum in renal failure to concentrations in excess of 0.2 mmol/L. This substance, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), has been shown to displace acidic drugs from albumin binding. The effects of CMPF on ligand binding were assessed in the following systems: (1) T 4 binding to T 4 -binding globulin (TBG) and transthyretin (TTR), (2) T 4 binding in undiluted serum, (3) T 4 -displacing potency of Fenclofenac, furosemide, diflunisal, and aspirin in undiluted serum, (4) serum binding of [ 14 C]-drug preparations, and (5) serum binding of [ 14 C]-oleic acid. CMPF had a minor direct effect on T 4 binding to TBG comparable in relative affinity to that of aspirin, ie, almost 7 orders of magnitude less than T 4 itself. CMPF alone at a concentration of 0.3 mmol/L, which produced only a 10% to 14% increase in free T 4 augmented the T 4 -displacing effects of high therapeutic concentrations of the various drugs in undiluted serum as follows: furosemide by 180%, Fenclofenac by 160%, diflunisal by 130%, and aspirin by 40%. In the presence of Fenclofenac, increments of CMPF from 0.075 to 0.3 mmol/L progressively augmented the T 4 -displacing effect of this drug, associated with a progressive increase in its calculated free concentration. CMPF also inhibited the binding of [ 14 C]-oleic acid, suggesting that in some situations CMPF could also indirectly influence thyroid hormone binding by increasing the unbound concentration of nonesterified fatty acids (NEFA), as previously described. CMPF at a concentration of 1 mmol/L did not inhibit charcoal or talc uptake of triiodothyronine (T 3 ) or T 4 . These findings indicate that CMPF can inhibit specific T 4 binding in serum by increasing the free concentrations of direct competitors. Such “cascade effects” on thyroid hormone binding could influence both the circulating concentrations and tissue delivery of thyroid hormones in renal failure and critical illness.

  • Interactions between oleic acid and drug competitors influence specific binding of thyroxine in serum.
    The Journal of clinical endocrinology and metabolism, 1991
    Co-Authors: Chen-fee Lim, Duncan J. Topliss, Andrea J. Curtis, John W. Barlow, Jan R. Stockigt
    Abstract:

    Long chain nonesterified fatty acids and various drugs may share albumin-binding sites in common. We questioned whether serum binding of T4 could be indirectly influenced by displacement of drug competitors from these sites by nonesterified fatty acids. The influence of oleic acid on drug-induced inhibition of [125I]T4 binding was measured by equilibrium dialysis, using undiluted serum in order to avoid dilution-related artefacts. Oleic acid (1 mmol/L) alone did not inhibit serum protein binding of T4, but this concentration augmented the inhibitory effects on T4 binding of diflunisal, mefenamic acid, meclofenamic acid, and aspirin. This effect increased with increasing concentrations of mefenamic acid, meclofenamic acid, and furosemide. The T4-displacing effect of Fenclofenac was not augmented by oleic acid. The mechanism of these interactions was studied by examining 1) oleic acid effects on drug binding, and 2) drug effects on oleic acid binding in undiluted serum. Increments in added oleic acid (0.5-2.0 mmol/L) progressively increased the mean unbound fractions of [14C]aspirin, [14C] diflunisal, and [14C]furosemide, but did not displace [14C]Fenclofenac. At the relevant total and free drug concentrations, the inhibitory effect of oleic acid on drug binding and its influence on drug-induced displacement of T4 were concordant in the order: meclofenamic acid greater than aspirin greater than mefenamic acid greater than diflunisal greater than furosemide greater than Fenclofenac. In contrast, drug-induced increases in the unbound fraction of [14C]oleic acid did not correlate with augmentation of T4 displacement. We conclude that synergistic effects of oleic acid and drugs on T4 binding result from drug displacement by oleic acid, rather than the reverse effect. Hence, substances that increase the unbound concentration of a competitor by displacing it from albumin can increase its T4-displacing potency. Interactions between various ligands may exert a greater hormone-displacing effect than the sum of each alone.

Chen-fee Lim - One of the best experts on this subject based on the ideXlab platform.

  • Drug effects on triiodothyronine uptake by rat anterior pituitary cells in vitro
    Experimental and clinical endocrinology & diabetes : official journal German Society of Endocrinology [and] German Diabetes Association, 1996
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    In nonthyroidal illness, numerous drugs such as glucocorticoids, dopamine, Fenclofenac, furosemide and diphenylhydantoin may modify the close inverse-feedback relationship between circulating thyroid hormones and TSH. Such effects could involve altered hypothalamic TRH secretion, a direct effect on TSH production by the thyrotroph, alterations in circulating free thyroid hormone concentrations, or changes in thyroid hormone uptake by the thyrotroph. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, the synthetic flavonoid EMD 21388, and diphenylhydantoin, on [125I]T3 cellular uptake in rat pituitary primary cell cultures. Uptake of [125I]T3 (cell-associated counts of washed cells) was measured at 15 min after the addition of 50 pmol/L [125I]T3 in protein-free medium (37 degrees C, pH 7.4). Uptake of [125I]T3 by pituitary cells was 6.0 +/- 1.7% of total counts (mean +/- SD, n = 18). Unlabeled T3 (10 mumols/L) displaced 92% of total uptake. The IC50 of unlabeled T3 for the displacement of [125I]T3 was 1.2 mumols/L. T4 and rT3 were approximately 10% as effective as T3 itself in inhibiting [125I]T3 uptake, while triac did not affect cellular [125I]T3 uptake. Inhibition of [125I]T3 uptake at drug concentrations of 100 mumols/L was seen with the diuretics, furosemide (9%), bumetanide (14%), piretanide (12%) and ethacrynic acid (76%), the NSAID, meclofenamic acid (35%) and Fenclofenac (52%), EMD 21388 (49%), and the anticonvulsant, diphenylhydantoin (23%). Aspirin, up to 500 mumols/L, had no effect on [125I]T3 uptake. Our results indicate that ethacrynic acid, meclofenamic acid, Fenclofenac, EMD 21388 and diphenylhydantoin affect plasma membrane T3 uptake in the pituitary. This potential influence on TSH release will be contrary to the previously-demonstrated direct inhibitory effect of these drugs on TSH release.

  • Effect of Loop Diuretics and Nonsteroidal Antiinflammatory Drugs on Thyrotropin Release by Rat Anterior Pituitary Cells In Vitro
    Metabolism: clinical and experimental, 1995
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    The close inverse-feedback relationship between serum free thyroxine (T4) and thyrotropin (TSH) is altered in some patients receiving therapeutic doses of drugs such as furosemide, Fenclofenac, and diphenylhydantoin. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, and diphenylhydantoin on TSH release in rat anterior pituitary cells in primary culture. TSH content of the culture medium was measured at 22 hours at 37°C either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) i either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) in medium containing 0.5% bovine serum albumin. The mean basal TSH release by pituitary cells was 6.2 ± 1.2 ng/mL (n = 10) and was not influenced by unlabeled triiodothyronine ([T3] 100 nmol/L) or any of the drugs tested at ≤ 400 μmol/L, except ethyacrynic acid. TRH 10 nmol/L increased mean TSH release by 346% ± 95% (n = 10). T3 1 and 100 nmol/L inhibited TRH-stimulated TSH release by 24% and 31%, respectively (P < .001), whereas TRH-stimulated TSH release was inhibited by 100 μmol/L meclofenamic acid (29%), Fenclofenac (28%), furosemide (24%), and diphenylhydantoin (48%) (P < .001 v TRH alone). Meclofenamic acid and furosemide (100 μmol/L) did not significantly alter the inhibitory effect of T3 1 nmol/L on TRH-stimulated TSH release. These in vitro studies suggest that meclofenamic acid, Fenclofenac, furosemide, and diphenylhydantoin could influence TSH release by attenuating the TSH response to TRH. This effect may influence T4-TSH relationships when these agents are used in vivo.

  • Alterations in hepatocyte uptake and plasma binding of thyroxine in nonthyroidal illness and caloric deprivation
    Trends in endocrinology and metabolism: TEM, 1995
    Co-Authors: Chen-fee Lim, Jan R. Stockigt, Georg Hennemann
    Abstract:

    Low plasma T(3) in severe illness is widely thought to be due principally to inhibition of 5'-deiodinase activity, but other factors also contribute to this response. Abnormal plasma constituents, namely, 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate in uremia, and elevated bilirubin and nonesterified fatty acids (NEFA) can impair T(4) transport into hepatocytes, thereby contributing to the lowering of plasma T(3). Assessment of possible endogenous or exogenous inhibitors of T(4) binding to plasma proteins is prone to dilution-dependent artifacts, which can lead to overestimation or underestimation of competitor potency, depending on experimental details. Because the potency of such competitors is a function of their free concentrations in undiluted serum, inhibitory activity may be enhanced by substances that impair their albumin binding. Oleic acid or CMPF can inhibit the effect of drugs such as furosemide or Fenclofenac.

  • A naturally occurring furan fatty acid enhances drug inhibition of thyroxine binding in serum
    Metabolism: clinical and experimental, 1993
    Co-Authors: Chen-fee Lim, Jan R. Stockigt, Andrea J. Curtis, John W. Barlow, Kenneth N. Wynne, Duncan J. Topliss
    Abstract:

    Abstract We studied the thyroxine (T 4 )-displacing effects of a naturally occurring, highly albumin-bound furanoid acid that accumulates in serum in renal failure to concentrations in excess of 0.2 mmol/L. This substance, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), has been shown to displace acidic drugs from albumin binding. The effects of CMPF on ligand binding were assessed in the following systems: (1) T 4 binding to T 4 -binding globulin (TBG) and transthyretin (TTR), (2) T 4 binding in undiluted serum, (3) T 4 -displacing potency of Fenclofenac, furosemide, diflunisal, and aspirin in undiluted serum, (4) serum binding of [ 14 C]-drug preparations, and (5) serum binding of [ 14 C]-oleic acid. CMPF had a minor direct effect on T 4 binding to TBG comparable in relative affinity to that of aspirin, ie, almost 7 orders of magnitude less than T 4 itself. CMPF alone at a concentration of 0.3 mmol/L, which produced only a 10% to 14% increase in free T 4 augmented the T 4 -displacing effects of high therapeutic concentrations of the various drugs in undiluted serum as follows: furosemide by 180%, Fenclofenac by 160%, diflunisal by 130%, and aspirin by 40%. In the presence of Fenclofenac, increments of CMPF from 0.075 to 0.3 mmol/L progressively augmented the T 4 -displacing effect of this drug, associated with a progressive increase in its calculated free concentration. CMPF also inhibited the binding of [ 14 C]-oleic acid, suggesting that in some situations CMPF could also indirectly influence thyroid hormone binding by increasing the unbound concentration of nonesterified fatty acids (NEFA), as previously described. CMPF at a concentration of 1 mmol/L did not inhibit charcoal or talc uptake of triiodothyronine (T 3 ) or T 4 . These findings indicate that CMPF can inhibit specific T 4 binding in serum by increasing the free concentrations of direct competitors. Such “cascade effects” on thyroid hormone binding could influence both the circulating concentrations and tissue delivery of thyroid hormones in renal failure and critical illness.

  • Interactions between oleic acid and drug competitors influence specific binding of thyroxine in serum.
    The Journal of clinical endocrinology and metabolism, 1991
    Co-Authors: Chen-fee Lim, Duncan J. Topliss, Andrea J. Curtis, John W. Barlow, Jan R. Stockigt
    Abstract:

    Long chain nonesterified fatty acids and various drugs may share albumin-binding sites in common. We questioned whether serum binding of T4 could be indirectly influenced by displacement of drug competitors from these sites by nonesterified fatty acids. The influence of oleic acid on drug-induced inhibition of [125I]T4 binding was measured by equilibrium dialysis, using undiluted serum in order to avoid dilution-related artefacts. Oleic acid (1 mmol/L) alone did not inhibit serum protein binding of T4, but this concentration augmented the inhibitory effects on T4 binding of diflunisal, mefenamic acid, meclofenamic acid, and aspirin. This effect increased with increasing concentrations of mefenamic acid, meclofenamic acid, and furosemide. The T4-displacing effect of Fenclofenac was not augmented by oleic acid. The mechanism of these interactions was studied by examining 1) oleic acid effects on drug binding, and 2) drug effects on oleic acid binding in undiluted serum. Increments in added oleic acid (0.5-2.0 mmol/L) progressively increased the mean unbound fractions of [14C]aspirin, [14C] diflunisal, and [14C]furosemide, but did not displace [14C]Fenclofenac. At the relevant total and free drug concentrations, the inhibitory effect of oleic acid on drug binding and its influence on drug-induced displacement of T4 were concordant in the order: meclofenamic acid greater than aspirin greater than mefenamic acid greater than diflunisal greater than furosemide greater than Fenclofenac. In contrast, drug-induced increases in the unbound fraction of [14C]oleic acid did not correlate with augmentation of T4 displacement. We conclude that synergistic effects of oleic acid and drugs on T4 binding result from drug displacement by oleic acid, rather than the reverse effect. Hence, substances that increase the unbound concentration of a competitor by displacing it from albumin can increase its T4-displacing potency. Interactions between various ligands may exert a greater hormone-displacing effect than the sum of each alone.

Duncan J. Topliss - One of the best experts on this subject based on the ideXlab platform.

  • Drug effects on triiodothyronine uptake by rat anterior pituitary cells in vitro
    Experimental and clinical endocrinology & diabetes : official journal German Society of Endocrinology [and] German Diabetes Association, 1996
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    In nonthyroidal illness, numerous drugs such as glucocorticoids, dopamine, Fenclofenac, furosemide and diphenylhydantoin may modify the close inverse-feedback relationship between circulating thyroid hormones and TSH. Such effects could involve altered hypothalamic TRH secretion, a direct effect on TSH production by the thyrotroph, alterations in circulating free thyroid hormone concentrations, or changes in thyroid hormone uptake by the thyrotroph. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, the synthetic flavonoid EMD 21388, and diphenylhydantoin, on [125I]T3 cellular uptake in rat pituitary primary cell cultures. Uptake of [125I]T3 (cell-associated counts of washed cells) was measured at 15 min after the addition of 50 pmol/L [125I]T3 in protein-free medium (37 degrees C, pH 7.4). Uptake of [125I]T3 by pituitary cells was 6.0 +/- 1.7% of total counts (mean +/- SD, n = 18). Unlabeled T3 (10 mumols/L) displaced 92% of total uptake. The IC50 of unlabeled T3 for the displacement of [125I]T3 was 1.2 mumols/L. T4 and rT3 were approximately 10% as effective as T3 itself in inhibiting [125I]T3 uptake, while triac did not affect cellular [125I]T3 uptake. Inhibition of [125I]T3 uptake at drug concentrations of 100 mumols/L was seen with the diuretics, furosemide (9%), bumetanide (14%), piretanide (12%) and ethacrynic acid (76%), the NSAID, meclofenamic acid (35%) and Fenclofenac (52%), EMD 21388 (49%), and the anticonvulsant, diphenylhydantoin (23%). Aspirin, up to 500 mumols/L, had no effect on [125I]T3 uptake. Our results indicate that ethacrynic acid, meclofenamic acid, Fenclofenac, EMD 21388 and diphenylhydantoin affect plasma membrane T3 uptake in the pituitary. This potential influence on TSH release will be contrary to the previously-demonstrated direct inhibitory effect of these drugs on TSH release.

  • Effect of Loop Diuretics and Nonsteroidal Antiinflammatory Drugs on Thyrotropin Release by Rat Anterior Pituitary Cells In Vitro
    Metabolism: clinical and experimental, 1995
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    The close inverse-feedback relationship between serum free thyroxine (T4) and thyrotropin (TSH) is altered in some patients receiving therapeutic doses of drugs such as furosemide, Fenclofenac, and diphenylhydantoin. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, and diphenylhydantoin on TSH release in rat anterior pituitary cells in primary culture. TSH content of the culture medium was measured at 22 hours at 37°C either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) i either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) in medium containing 0.5% bovine serum albumin. The mean basal TSH release by pituitary cells was 6.2 ± 1.2 ng/mL (n = 10) and was not influenced by unlabeled triiodothyronine ([T3] 100 nmol/L) or any of the drugs tested at ≤ 400 μmol/L, except ethyacrynic acid. TRH 10 nmol/L increased mean TSH release by 346% ± 95% (n = 10). T3 1 and 100 nmol/L inhibited TRH-stimulated TSH release by 24% and 31%, respectively (P < .001), whereas TRH-stimulated TSH release was inhibited by 100 μmol/L meclofenamic acid (29%), Fenclofenac (28%), furosemide (24%), and diphenylhydantoin (48%) (P < .001 v TRH alone). Meclofenamic acid and furosemide (100 μmol/L) did not significantly alter the inhibitory effect of T3 1 nmol/L on TRH-stimulated TSH release. These in vitro studies suggest that meclofenamic acid, Fenclofenac, furosemide, and diphenylhydantoin could influence TSH release by attenuating the TSH response to TRH. This effect may influence T4-TSH relationships when these agents are used in vivo.

  • A naturally occurring furan fatty acid enhances drug inhibition of thyroxine binding in serum
    Metabolism: clinical and experimental, 1993
    Co-Authors: Chen-fee Lim, Jan R. Stockigt, Andrea J. Curtis, John W. Barlow, Kenneth N. Wynne, Duncan J. Topliss
    Abstract:

    Abstract We studied the thyroxine (T 4 )-displacing effects of a naturally occurring, highly albumin-bound furanoid acid that accumulates in serum in renal failure to concentrations in excess of 0.2 mmol/L. This substance, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), has been shown to displace acidic drugs from albumin binding. The effects of CMPF on ligand binding were assessed in the following systems: (1) T 4 binding to T 4 -binding globulin (TBG) and transthyretin (TTR), (2) T 4 binding in undiluted serum, (3) T 4 -displacing potency of Fenclofenac, furosemide, diflunisal, and aspirin in undiluted serum, (4) serum binding of [ 14 C]-drug preparations, and (5) serum binding of [ 14 C]-oleic acid. CMPF had a minor direct effect on T 4 binding to TBG comparable in relative affinity to that of aspirin, ie, almost 7 orders of magnitude less than T 4 itself. CMPF alone at a concentration of 0.3 mmol/L, which produced only a 10% to 14% increase in free T 4 augmented the T 4 -displacing effects of high therapeutic concentrations of the various drugs in undiluted serum as follows: furosemide by 180%, Fenclofenac by 160%, diflunisal by 130%, and aspirin by 40%. In the presence of Fenclofenac, increments of CMPF from 0.075 to 0.3 mmol/L progressively augmented the T 4 -displacing effect of this drug, associated with a progressive increase in its calculated free concentration. CMPF also inhibited the binding of [ 14 C]-oleic acid, suggesting that in some situations CMPF could also indirectly influence thyroid hormone binding by increasing the unbound concentration of nonesterified fatty acids (NEFA), as previously described. CMPF at a concentration of 1 mmol/L did not inhibit charcoal or talc uptake of triiodothyronine (T 3 ) or T 4 . These findings indicate that CMPF can inhibit specific T 4 binding in serum by increasing the free concentrations of direct competitors. Such “cascade effects” on thyroid hormone binding could influence both the circulating concentrations and tissue delivery of thyroid hormones in renal failure and critical illness.

  • Interactions between oleic acid and drug competitors influence specific binding of thyroxine in serum.
    The Journal of clinical endocrinology and metabolism, 1991
    Co-Authors: Chen-fee Lim, Duncan J. Topliss, Andrea J. Curtis, John W. Barlow, Jan R. Stockigt
    Abstract:

    Long chain nonesterified fatty acids and various drugs may share albumin-binding sites in common. We questioned whether serum binding of T4 could be indirectly influenced by displacement of drug competitors from these sites by nonesterified fatty acids. The influence of oleic acid on drug-induced inhibition of [125I]T4 binding was measured by equilibrium dialysis, using undiluted serum in order to avoid dilution-related artefacts. Oleic acid (1 mmol/L) alone did not inhibit serum protein binding of T4, but this concentration augmented the inhibitory effects on T4 binding of diflunisal, mefenamic acid, meclofenamic acid, and aspirin. This effect increased with increasing concentrations of mefenamic acid, meclofenamic acid, and furosemide. The T4-displacing effect of Fenclofenac was not augmented by oleic acid. The mechanism of these interactions was studied by examining 1) oleic acid effects on drug binding, and 2) drug effects on oleic acid binding in undiluted serum. Increments in added oleic acid (0.5-2.0 mmol/L) progressively increased the mean unbound fractions of [14C]aspirin, [14C] diflunisal, and [14C]furosemide, but did not displace [14C]Fenclofenac. At the relevant total and free drug concentrations, the inhibitory effect of oleic acid on drug binding and its influence on drug-induced displacement of T4 were concordant in the order: meclofenamic acid greater than aspirin greater than mefenamic acid greater than diflunisal greater than furosemide greater than Fenclofenac. In contrast, drug-induced increases in the unbound fraction of [14C]oleic acid did not correlate with augmentation of T4 displacement. We conclude that synergistic effects of oleic acid and drugs on T4 binding result from drug displacement by oleic acid, rather than the reverse effect. Hence, substances that increase the unbound concentration of a competitor by displacing it from albumin can increase its T4-displacing potency. Interactions between various ligands may exert a greater hormone-displacing effect than the sum of each alone.

Nicole M. Loidl - One of the best experts on this subject based on the ideXlab platform.

  • Drug effects on triiodothyronine uptake by rat anterior pituitary cells in vitro
    Experimental and clinical endocrinology & diabetes : official journal German Society of Endocrinology [and] German Diabetes Association, 1996
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    In nonthyroidal illness, numerous drugs such as glucocorticoids, dopamine, Fenclofenac, furosemide and diphenylhydantoin may modify the close inverse-feedback relationship between circulating thyroid hormones and TSH. Such effects could involve altered hypothalamic TRH secretion, a direct effect on TSH production by the thyrotroph, alterations in circulating free thyroid hormone concentrations, or changes in thyroid hormone uptake by the thyrotroph. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, the synthetic flavonoid EMD 21388, and diphenylhydantoin, on [125I]T3 cellular uptake in rat pituitary primary cell cultures. Uptake of [125I]T3 (cell-associated counts of washed cells) was measured at 15 min after the addition of 50 pmol/L [125I]T3 in protein-free medium (37 degrees C, pH 7.4). Uptake of [125I]T3 by pituitary cells was 6.0 +/- 1.7% of total counts (mean +/- SD, n = 18). Unlabeled T3 (10 mumols/L) displaced 92% of total uptake. The IC50 of unlabeled T3 for the displacement of [125I]T3 was 1.2 mumols/L. T4 and rT3 were approximately 10% as effective as T3 itself in inhibiting [125I]T3 uptake, while triac did not affect cellular [125I]T3 uptake. Inhibition of [125I]T3 uptake at drug concentrations of 100 mumols/L was seen with the diuretics, furosemide (9%), bumetanide (14%), piretanide (12%) and ethacrynic acid (76%), the NSAID, meclofenamic acid (35%) and Fenclofenac (52%), EMD 21388 (49%), and the anticonvulsant, diphenylhydantoin (23%). Aspirin, up to 500 mumols/L, had no effect on [125I]T3 uptake. Our results indicate that ethacrynic acid, meclofenamic acid, Fenclofenac, EMD 21388 and diphenylhydantoin affect plasma membrane T3 uptake in the pituitary. This potential influence on TSH release will be contrary to the previously-demonstrated direct inhibitory effect of these drugs on TSH release.

  • Effect of Loop Diuretics and Nonsteroidal Antiinflammatory Drugs on Thyrotropin Release by Rat Anterior Pituitary Cells In Vitro
    Metabolism: clinical and experimental, 1995
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    The close inverse-feedback relationship between serum free thyroxine (T4) and thyrotropin (TSH) is altered in some patients receiving therapeutic doses of drugs such as furosemide, Fenclofenac, and diphenylhydantoin. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, and diphenylhydantoin on TSH release in rat anterior pituitary cells in primary culture. TSH content of the culture medium was measured at 22 hours at 37°C either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) i either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) in medium containing 0.5% bovine serum albumin. The mean basal TSH release by pituitary cells was 6.2 ± 1.2 ng/mL (n = 10) and was not influenced by unlabeled triiodothyronine ([T3] 100 nmol/L) or any of the drugs tested at ≤ 400 μmol/L, except ethyacrynic acid. TRH 10 nmol/L increased mean TSH release by 346% ± 95% (n = 10). T3 1 and 100 nmol/L inhibited TRH-stimulated TSH release by 24% and 31%, respectively (P < .001), whereas TRH-stimulated TSH release was inhibited by 100 μmol/L meclofenamic acid (29%), Fenclofenac (28%), furosemide (24%), and diphenylhydantoin (48%) (P < .001 v TRH alone). Meclofenamic acid and furosemide (100 μmol/L) did not significantly alter the inhibitory effect of T3 1 nmol/L on TRH-stimulated TSH release. These in vitro studies suggest that meclofenamic acid, Fenclofenac, furosemide, and diphenylhydantoin could influence TSH release by attenuating the TSH response to TRH. This effect may influence T4-TSH relationships when these agents are used in vivo.

Jennifer A. Kennedy - One of the best experts on this subject based on the ideXlab platform.

  • Drug effects on triiodothyronine uptake by rat anterior pituitary cells in vitro
    Experimental and clinical endocrinology & diabetes : official journal German Society of Endocrinology [and] German Diabetes Association, 1996
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    In nonthyroidal illness, numerous drugs such as glucocorticoids, dopamine, Fenclofenac, furosemide and diphenylhydantoin may modify the close inverse-feedback relationship between circulating thyroid hormones and TSH. Such effects could involve altered hypothalamic TRH secretion, a direct effect on TSH production by the thyrotroph, alterations in circulating free thyroid hormone concentrations, or changes in thyroid hormone uptake by the thyrotroph. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, the synthetic flavonoid EMD 21388, and diphenylhydantoin, on [125I]T3 cellular uptake in rat pituitary primary cell cultures. Uptake of [125I]T3 (cell-associated counts of washed cells) was measured at 15 min after the addition of 50 pmol/L [125I]T3 in protein-free medium (37 degrees C, pH 7.4). Uptake of [125I]T3 by pituitary cells was 6.0 +/- 1.7% of total counts (mean +/- SD, n = 18). Unlabeled T3 (10 mumols/L) displaced 92% of total uptake. The IC50 of unlabeled T3 for the displacement of [125I]T3 was 1.2 mumols/L. T4 and rT3 were approximately 10% as effective as T3 itself in inhibiting [125I]T3 uptake, while triac did not affect cellular [125I]T3 uptake. Inhibition of [125I]T3 uptake at drug concentrations of 100 mumols/L was seen with the diuretics, furosemide (9%), bumetanide (14%), piretanide (12%) and ethacrynic acid (76%), the NSAID, meclofenamic acid (35%) and Fenclofenac (52%), EMD 21388 (49%), and the anticonvulsant, diphenylhydantoin (23%). Aspirin, up to 500 mumols/L, had no effect on [125I]T3 uptake. Our results indicate that ethacrynic acid, meclofenamic acid, Fenclofenac, EMD 21388 and diphenylhydantoin affect plasma membrane T3 uptake in the pituitary. This potential influence on TSH release will be contrary to the previously-demonstrated direct inhibitory effect of these drugs on TSH release.

  • Effect of Loop Diuretics and Nonsteroidal Antiinflammatory Drugs on Thyrotropin Release by Rat Anterior Pituitary Cells In Vitro
    Metabolism: clinical and experimental, 1995
    Co-Authors: Chen-fee Lim, Nicole M. Loidl, Jennifer A. Kennedy, Duncan J. Topliss, Jan R. Stockigt
    Abstract:

    The close inverse-feedback relationship between serum free thyroxine (T4) and thyrotropin (TSH) is altered in some patients receiving therapeutic doses of drugs such as furosemide, Fenclofenac, and diphenylhydantoin. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, and diphenylhydantoin on TSH release in rat anterior pituitary cells in primary culture. TSH content of the culture medium was measured at 22 hours at 37°C either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) i either with or without thyrotropin-releasing hormone ([TRH] 10 nmol/L) in medium containing 0.5% bovine serum albumin. The mean basal TSH release by pituitary cells was 6.2 ± 1.2 ng/mL (n = 10) and was not influenced by unlabeled triiodothyronine ([T3] 100 nmol/L) or any of the drugs tested at ≤ 400 μmol/L, except ethyacrynic acid. TRH 10 nmol/L increased mean TSH release by 346% ± 95% (n = 10). T3 1 and 100 nmol/L inhibited TRH-stimulated TSH release by 24% and 31%, respectively (P < .001), whereas TRH-stimulated TSH release was inhibited by 100 μmol/L meclofenamic acid (29%), Fenclofenac (28%), furosemide (24%), and diphenylhydantoin (48%) (P < .001 v TRH alone). Meclofenamic acid and furosemide (100 μmol/L) did not significantly alter the inhibitory effect of T3 1 nmol/L on TRH-stimulated TSH release. These in vitro studies suggest that meclofenamic acid, Fenclofenac, furosemide, and diphenylhydantoin could influence TSH release by attenuating the TSH response to TRH. This effect may influence T4-TSH relationships when these agents are used in vivo.