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Biomedical subjects

M T Hays

Publications and source records attributed to M T Hays.

At least 37 records · Page 2Linked to original sources
PubMed1991

Localization of human thyroxine absorption.

The distribution of intestinal absorption of 131I-labeled thyroxine (T4*) was studied in 4 normal subjects after oral and i.v. T4*, given in separate experimental sessions. In addition to collection of time-activity curves for plasma T4* from the two sessions, distribution and transport of T4* through the gut was quantified by external imaging. Time-activity curves were obtained for the stomach, duodenum, and upper jejunoileum. A multicompartmental model for systemic T4, with three distribution compartments and a single exit route, was employed. Additional, gastrointestinal, compartments were introduced. The stomach data were fitted to a model with three compartments, two for transport and a small sink of gastric activity that does not interact with the absorptive sites. Transfer from the duodenum to the upper jejunoileum and from the upper to the lower jejunoileum was modeled from fits to the peak T4* activities in the images of the duodenum and upper jejunoileum. The rate of transfer from the lower jejunoileum into more distal intestinal sites was fixed, but the impact on the results of using various values for this parameter was analyzed. The model calculations of absorption (mean +/- SD for 3 of the subjects) are duodenum, 15 +/- 5%, upper jejunoileum, 29 +/- 14%, and lower jejunoileum, 24 +/- 11%. The fourth subject, whose global absorption was abnormally low for uncertain reasons, had 17% absorption from the duodenum, 9% from the upper jejunoileum and none from the lower jejunoileum. Model projections mimicking clinical gut abnormalities known to affect T4 absorption were compatible with the results of published studies.

Administration, Oral↗
PubMed1988

Equilibrium dialysis studies of plasma binding of thyroxine, triiodothyronine and their glucuronide and sulfate conjugates in human and cat plasma.

Binding of thyroxine (T4), triiodothyronine (T3) and their glucuronide and sulfate conjugates, T4G, T3G, T4S and T3S, was assessed by equilibrium dialysis in plasma from 6 euthyroid humans and 5 euthyroid cats. In humans, the dialyzable percentages of T4, T4G and T4S were 0.029 +/- 0.003 (mean +/- S.D.), 0.14 +/- 0.04 and 0.08 +/- 0.02 respectively. For T3, T3G and T3S they were 0.31 +/- 0.04, 0.33 +/- 0.07 and 0.22 +/- 0.02. In cats, the corresponding values for T4, T4G and T4S were 0.057 +/- 0.009, 0.20 +/- 0.10 and 0.53 +/- 0.04; for T3, T3G and T3S they were 0.47 +/- 0.08, 0.51 +/- 0.11, and 0.53 +/- 0.11. We conclude that glucuronide conjugation has little or no inhibiting effect on the plasma binding of T3, and that T3S is actually more tightly bound than T3 in human (but not feline) plasma. On the other hand, conjugation to either the glucuronide or the sulfate markedly reduced T4 binding in plasma from both species.

Adult↗
PubMed1988

A multicompartmental model for iodide, thyroxine, and triiodothyronine metabolism in normal and spontaneously hyperthyroid cats.

A comprehensive multicompartmental kinetic model was developed to account for the distribution and metabolism of simultaneously injected radioactive iodide (iodide*), T3 (T3*), and T4 (T4*) in six normal and seven spontaneously hyperthyroid cats. Data from plasma samples (analyzed by HPLC), urine, feces, and thyroid accumulation were incorporated into the model. The submodels for iodide*, T3*, and T4* all included both a fast and a slow exchange compartment connecting with the plasma compartment. The best-fit iodide* model also included a delay compartment, presumed to be pooling of gastrosalivary secretions. This delay was 62% longer in the hyperthyroid cats than in the euthyroid cats. Unexpectedly, all of the exchange parameters for both T4 and T3 were significantly slowed in hyperthyroidism, possibly because the hyperthyroid cats were older. None of the plasma equivalent volumes of the exchange compartments of iodide*, T3*, or T4* was significantly different in the hyperthyroid cats, although the plasma equivalent volume of the fast T4 exchange compartments were reduced. Secretion of recycled T4* from the thyroid into the plasma T4* compartment was essential to model fit, but its quantity could not be uniquely identified in the absence of multiple thyroid data points. Thyroid secretion of T3* was not detectable. Comparing the fast and slow compartments, there was a shift of T4* deiodination into the fast exchange compartment in hyperthyroidism. Total body mean residence times (MRTs) of iodide* and T3* were not affected by hyperthyroidism, but mean T4* MRT was decreased 23%. Total fractional T4 to T3 conversion was unchanged in hyperthyroidism, although the amount of T3 produced by this route was increased nearly 5-fold because of higher concentrations of donor stable T4. Analysis of the data indicates that the increased overall T4* turnover (decreased MRT) in hyperthyroidism is due to increased losses through pathways other than T3 formation. Conjugation, with subsequent deiodination, is proposed as one possibly important pathway. Results of this multicompartmental analysis are compared with those of noncompartmental analysis of the same data and with results of similar model analyses in other species.

Animals↗
PubMed1988

Thyroid hormone and the gut.

The gastrointestinal tract interacts actively with the thyroid hormones, T4 and T3. Both T4 and T3 are absorbed well but incompletely from the gut, and many factors affect this absorption. The mechanism of absorption is unknown. It is decreased in most malabsorption conditions, but is increased in the postgastrojejunotomy syndrome. It may involve conjugation to the glucuronide forms (T4G and T3G) in the mucosal cell with subsequent deconjugation prior to appearance in the portal vein blood. Absorption appears to be reduced in the presence of excess T4, and increased in hypothyroidism. The liver takes up a large fraction of the T4 and T3 from its circulation and returns a portion of the portal hormone back to the gut via the bile. There is also direct T4 and T3 secretion into the gut from the mesenteric circulation. Recent studies suggest that the gut plays a major role as a reservoir for the thyroid hormones, especially for T3, and that it may also play a role in the regulation of hormone activity.

Animals↗
PubMed1988

Predictive value of tracer studies for 131I treatment in hyperthyroid cats.

In 76 cats with hyperthyroidism, peak thyroidal radioiodine (131I) uptakes and effective half-lives were determined after administration of tracer and therapeutic activities of 131I. In 6 additional hyperthyroid cats, only peak thyroidal uptakes after administration of tracer and therapeutic activities of 131I were determined. Good correlation was found between peak thyroidal uptakes of tracer and therapeutic 131I; however, only fair correlation was observed between effective half-lives. In 79% of the cats, the effective half-life for therapeutic 131I was longer than that for tracer 131I. After administration of therapeutic activity of 131I, monoexponential and biphasic decay curves were observed in 51 and 16 cats, respectively. Using therapeutic kinetic data, radiation doses to the thyroid gland were calculated retrospectively on the basis of 2 methods for determining the activity of 131I administered: (1) actual administration of tracer-compensated activity and (2) hypothetic administration of uniform activity (3 mCi). Because of the good predictive ability of tracer kinetic data for the therapeutic kinetic data, the tracer-compensated radiation doses came significantly (P = 0.008) closer to the therapeutic goal than did the uniform-activity doses. In addition, the use of tracer kinetic information reduced the extent of the tendency for consistently high uniform-activity doses. A manual method for acquiring tracer kinetic data was developed and was an acceptable alternative to computerized techniques. Adoption of this method gives individuals and institutions with limited finances the opportunity to characterize the iodine kinetics in cats before proceeding with administration of therapeutic activities of 131I.

Animals↗
PubMed1987

Preparation and separation of the glucuronide and sulfate conjugates of thyroxine and triiodothyronine.

An enzymatic method for synthesis of labelled thyroxine glucuronide (T4G) and triiodothyronine glucuronide (T3G) from labelled thyroxine (T4) and triiodothyronine (T3) is presented. The synthetic glucuronides are completely digested by beta-glucuronidase, with recovery of the parent T4 or T3. They have distinctive elution patterns on HPLC and on Sephadex G25 chromatography, and can be clearly separated from T4 and T3 as well as from synthetic T4 sulfate (T4S) and T3 sulfate (T3S). On LH 20 chromatography, elution of T4G and T3G is intermediate between that of T4 and T3 and that of T4S and T3S. T3G can be well separated from other thyronines by HPLC alone, but T4G coelutes with rT3 on HPLC; these are then separated by adding a Sephadex G25 chromatography step. Biosynthetic 131I-T3G and 125I-T4G from the bile of a cat given 131I-T3 and 125I-T4 had similar HPLC chromatographic patterns to those of synthetic T3G and T4G. That the identified peaks from analysis of the bile were indeed T3G and T4G was confirmed by recovery of the parent T3 and T4 after beta-glucuronidase digestion.

Animals↗
PubMed1987

Effect of sampling site on early kinetics of blood radioiodide and pertechnetate.

Radioiodide (I) and radiopertechnetate (TcO4) were sampled simultaneously from left ventricle, right atrium, and femoral vein early after intravenous injection to pentobarbital sodium-anesthetized cats. Concentrations of both tracers in femoral vein blood was lower than in left ventricular (arterial) blood, with rapid narrowing of the differences over 20 min and gradual approach to steady state. Right atrial blood concentrations were intermediate. When these data were fitted to three-compartment mamillary models, representing blood and tissue pools, compartment size and kinetics differed according to which sampling site was taken as representative of each cat's blood. We have developed a model incorporating subcompartmentalization of the blood with an exchange compartment connecting to the pulmonary circulation as well as compartments exchanging with peripheral sites. With the use of this model, all data sets fitted well. The pulmonary exchange compartment and a large rapid exchange compartment in the femoral vein drainage areas are essential to reconciling the differences among sampling sites.

Animals↗
PubMed1987

Peripheral metabolism of thyroid hormones and iodide in healthy and hyperthyroid cats.

The metabolic clearance rate, volume of distribution, and fractional clearance rate of thyroxine (T4), triiodothyronine (T3), and iodide were calculated for 6 healthy and 7 hyperthyroid cats, using single-compartmental and noncompartmental methods of analysis. The mean T4 volume of distribution of the hyperthyroid cats was 32.0% less than that of the healthy cats; it was the only variable that was significantly different (P less than 0.05) between these 2 groups of cats. The mean fractional clearance rate of T4 in the hyperthyroid cats was 53.2% greater than that in the healthy cats, but this difference was not significant. Hyperthyroid cats had no significant differences in T3 or iodide kinetic variables when compared with those in healthy cats. Single-compartmental analysis significantly overestimated T4 kinetic variables of healthy cats and T4, T3, and iodide kinetic variables of hyperthyroid cats when compared with the noncompartmental method of analysis.

Animals↗
PubMed1986

Multicompartmental analysis of the kinetics of radioiodinated monoclonal antibody in patients with cancer.

A conceptual biologic model was developed and used to analyze the behavior of 123I-Lym-1 monoclonal antibody against African human B cell lymphoma in patients with B cell lymphoma. Originally, the observed data could not be simulated with parameters for homologous immunoglobulins reported in the literature because of a major processor that was capable of distinguishing this murine immunoglobulin from the patient's own immunoglobulins. With a nonlinear parametric model, the data observed in patients could be fitted to the model. The nonlinear parameter determined the transfer of antibody from the intravascular to a processor compartment, primarily the liver. This transfer was a function of the number of free receptors in the processor. Model simulated curves for the time course of concentration of antibody in the blood for different amounts of injected antibody revealed that blood clearance of radiolabeled antibody was profoundly decreased by increased amount of injected antibody. This model provides an explanation for the observations that tumor imaging is improved with injection of larger amounts of antibody, and a basis for modifying the pharmacokinetic behavior of an antibody in order to optimize radioimmunodiagnosis and radioimmunotherapy.

Antibodies, Monoclonal↗
PubMed1985

Requirements for a treatment planning system for radioimmunotherapy.

Cancer-seeking antibodies carrying radionuclides can, in theory, be very powerful agents for the radiotherapy of cancer. However, as with all radiotherapy, the undesired dose to critical normal organs is the limiting factor that determines success or failure. The distribution of radiation dose in cancer and noncancer tissue is highly dependent on choices the therapist can make: choices of the antigens to be targeted, choices of the antibodies or antibody fragments to be used, choices of radionuclides, of amounts, of timing, and other electives. New technologies, especially of monoclonal antibody production, make the options myriad. Optimization of this therapy depends on a foreknowledge of the radiation dose distributions to be expected. The necessary data can be acquired by established tracer techniques, in individual patients, for particular treatment selections. These tracer techniques can now be implemented by advanced equipment for quantitative, tomographic radionuclide imaging and strengthened by dynamic modeling of the physiological parameters which govern radionuclide distribution, and hence radiation dose distribution.

Animals↗
PubMed1985

Radiation dosimetry of radioiodinated thyroid hormones.

A physiologically based compartmental model for T4 and T3 metabolism in man was used to generate time-activity curves for residence of radioiodine in key organs. T4 and T3 labeled with 123I, 124I, 125I, and 131I were studied. Conditions modeled included radioactive iodine uptake (RAIU) values of 0%, 1%, 5%, 15% and 25%, and RAIU of 15% combined with various degrees of pharmacologic block of thyroidal RAIU. Using the MIRD "S" tables, rad doses were generated for each condition. While the shapes of the time-activity curves varied widely with alterations in physical and biological turnover and with changes in steady-state due to iodine administration, it was possible to calculate overall effective half-lives for each organ of interest from the integral of the time-activity curve projected by solution of the model. This overall effective half-life of the hormone for the body's exchangeable hormone compartments correlated well with calculated radiation dose to the thyroid in the unblocked state. With progressive degrees of iodine block, this correlation persisted, though with proportionately reduced thyroid radiation doses. Use and manipulation of a compartmental model, rather than the usual multiexponential model, for radiation dosimetry facilitates conceptualization and the projection of the effects of interventions such as iodide block.

Humans↗
PubMed1981

A kinetic model of human thyroid hormones and their conversion products.

We have examined the in vivo distribution and metabolism of radiolabeled T4 and T3 in 14 normal subjects using a kinetic model. Tracer amounts of [131I]T4 and [125I]T3 were injected simultaneously, and plasma samples were obtained for up to 7 days thereafter. Separation of these samples by thin layer chromatography yielded kinetic curves for 131I- and 125I-labeled T4, T3, iodide, and iodoprotein, which were then used to develop a kinetic model. The model includes several features. 1) Submodels were developed for T4, T3, iodide, and iodoprotein which simultaneously fit the observed data. 2) Two other submodels were needed for data fit, the first representing rT3, the other representing other intermediates, including the various diiodothyronines. The latter submodel was patterned initially after 3,3'-diiodothyronine kinetics. It was required to account for the delay in appearance of labeled iodide produced from the degradation of T4, and rT3 and proved to be essential for the successful fit of the data. 3) The model accounts for the conversion of T4 to T3 and rT3. Even though rT3 is quantitatively significant as a degradation pathway for T4, its presence does not contribute significantly to total plasma radioactivity after T4 administration because of its rapid turnover in comparison with T4. 4) The small amount of iodoprotein formed is a major contributor to total plasma radioactivity within 3 days after T3 administration. 5) The model permits the elimination of two methodological errors: that due to the presence of labeled iodide, T3, or T4 contaminants in the administered labeled hormones, and that due to the small amount of cross-over between thin layer chromatography peaks. The model provides a concise description of our current understanding of thyroid hormone metabolism and suggests areas where further information is required.

Adult↗
PubMed1980

Distribution of subcutaneous thyroxine, triiodothyronine, and albumin in man: comparison with intravenous administration using a kinetic model.

Distributional kinetics of radioiodinated T4 (T4), T3 (T3), and albumin (RISA), after simultaneous administration by the sc and iv routes of 125I- and 131I-labeled compounds, were measured in normal subjects. Data were analyzed by fitting them, using the SAAM technique, to models with three compartments for the iv administered compounds and a fourth compartment for the site of the sc injection. The radiopharmaceuticals administered sc transfered by first order kinetics from the injection site to plasma with half-lives of 20.4, 5.6, and 63.0 h for T4, T3, and RISA, respectively. Percentages of 3.3, 1.2, and 2.1 of the sc dose appeared directly in the vascular compartment. In some, but not all, studies with sc T4 and RISA, a portion of the disappearance from the sc site appeared to be due to in situ deiodination, rather than to transfer of the parent compound into the circulation. After T3 administration, both iv and sc, a product with kinetics similar to RISA appeared, accounting for 3% of the T3 decay for the averaged data and ranging from 0.9--19.4% in individual cases. Comparing T3 kinetic analysis by this technique (in which the iodoprotein byproduct is accounted for by modeling instead of chemical separation), the resulting parameters are similar to those reported by others after chemical separation of T3. Judging by compartment size and distributional kinetics, the model compartments derived for iv administration of these compounds appear to represent the vascular pool (central compartment), the hepatic and renal distribution sites (fast peripheral compartment), and other peripheral tissues (slow peripheral compartment). The latter, which presumably includes the site of sc injection, transfers into the central compartment at approximately the same rate as does the compartment representing the sc injection site itself.

Adult↗
PubMed1980

Measurement method for radioactive thyroxine, triiodothyronine, iodide, and iodoprotein in samples with low activity.

A method is described that incorporates resin extraction and thin layer chromatography to isolate and separate radioiodinated thyroxine (T4), triiodothyronine (T3), iodoprotein, and iodide in samples of human plasma up to 3 ml. Tracer studies using this method showed that reverse T3 and 3',5' diiodothyronine (T2), as well as T4, were detected in the "T4 fraction," and that 3-3' T2 and 3' monoiodothyronine, as well as T3, were detected in the "T3 fraction." Monoiodotyrosine and diiodotyrosine (DIT) migrated more slowly than did T4 on the chromatogram, and a large amount of DIT was in the unextracted "iodoprotein fraction." Kinetic studies in 14 normal subjects given intravenous commercial [125I]T3 (T3*) and [131I]T4 (T4*), confirmed the quantitative importance of an iodoprotein in later samples after T3* administration, and its presence after T4*. T4* contamination of commercial T3* also became quantitatively important. On the other hand, despite confirmation of in vivo conversion of T4* to T3*, T3* contributed little quantitatively to the total concentration of radioactivity present even late after T4* injection, due to the more rapid turnover and greater distribution volume of T3*.

Chromatography, Thin Layer↗