T4 Absorption Research Articles

Levothyroxine malabsorption following sleeve gastrectomy.

Oral levothyroxine (LT4) is prescribed worldwide for hypothyroidism. Bariatric surgery for patients with obesity has shown a substantial, long-term weight loss and considerable improvement of obesity-related diseases. LT4 malabsorption represents a significant cause of refractory hypothyroidism, well known after malabsorptive bariatric surgery such as Roux-en-Y gastric bypass. However, few studies have shown an increase in oral LT4 needed after sleeve gastrectomy. We present a 47-year-old woman with class III obesity and a history of papillary thyroid cancer, with an excellent biochemical and structural response after total thyroidectomy and radioactive iodine. She underwent sleeve gastrectomy 3 years later and developed refractory hypothyroidism despite taking high doses of oral LT4 and ensuring compliance. The T4 absorption test confirmed gastrointestinal LT4 malabsorption. She was initiated on intramuscular LT4 and oral T3 (liothyronine) with improving symptoms and levels of thyroid-stimulating hormone. Monitoring thyroid function tests is essential after bariatric surgery, including sleeve gastrectomy. Oral LT4 malabsorption should be considered in cases of refractory hypothyroidism. The T4 absorption test is a useful tool for distinguishing true malabsorption from pseudo-malabsorption. Decreased LT4 absorption after bariatric surgery might be explained by higher gastric pH and reduced stomach volume (impaired dissolution) and by interference with food, vitamin/mineral supplements or other drugs. When LT4 malabsorption is confirmed, a trial of other oral formulations (LT4 tablet crushed, soft gel or liquid preparation) or parenteral administrations is suggested.

7370 Review of the Literature, and Report of a Series of Patients with Lactose Intolerance and Levothyroxine Malabsorption in Treatment with Liquid L-T4

Abstract Disclosure: S. Ferrari: None. A. Patrizio: None. V. Mazzi: None. F. Ragusa: None. C. Botrini: None. G. Elia: None. E. Balestri: None. E. Barozzi: None. L. Rugani: None. F. Bracchitta: None. G. Stoppini: None. G. Frenzilli: None. E. Baldini: None. C. Virili: None. S. Benvenga: None. P. Fallahi: None. A. Antonelli: None. Intolerance to lactose-containing foods is frequent, with a prevalence of 7-20% in Caucasians, and of 80-95% among Native Americans. Therefore, lactose intolerance (LI) issue needs to be taken in account in the management of hypothyroid patients needing large doses of levothyroxine (L-T4) (> 1.7-2 μg/kg/day) to achieve euthyroidism. Indeed, the absorption of oral T4 may be affected in patients with LI, by following a diet containing lactose, whereas it is resulted to be improved with a lactose-free diet. Lactose is often present as a supplementary ingredient in many commercially available drugs, as L-T4 preparations. In susceptible individuals, drugs containing lactose can cause LI symptoms, and lactose in L-T4 preparations could impair thyroxine absorption. Moreover, it has been shown that patients with LI requiring an increased dosage of L-T4 benefit from a treatment with a lactose-free L-T4 formulation. The lactose-free liquid L-T4 formulation is able to circumvent LI malabsorption leading to the normalization of thyroid-stimulating hormone (TSH) in patients with subclinical hypothyroidism, and long term stable TSH levels. Further studies will be needed to evaluate the liquid L-T4 formulation in larger numbers of patients with hypothyroidism and LI. Presentation: 6/3/2024

Increased Absorption of Thyroxine in a Murine Model of Hypothyroidism Using Water/CO2 Nanobubbles.

Thyroxine (T4) is a drug extensively utilized for the treatment of hypothyroidism. However, the oral absorption of T4 presents certain limitations. This research investigates the efficacy of CO2 nanobubbles in water as a potential oral carrier for T4 administration to C57BL/6 hypothyroid mice. Following 18 h of fasting, the formulation was administered to the mice, demonstrating that the combination of CO2 nanobubbles and T4 enhanced the drug's absorption in blood serum by approximately 40%. To comprehend this observation at a molecular level, we explored the interaction mechanism through which T4 engages with the CO2 nanobubbles, employing molecular simulations, semi-empirical quantum mechanics, and PMF calculations. Our simulations revealed a high affinity of T4 for the water-gas interface, driven by additive interactions between the hydrophobic region of T4 and the gas phase and electrostatic interactions of the polar groups of T4 with water at the water-gas interface. Concurrently, we observed that at the water-gas interface, the cluster of T4 formed in the water region disassembles, contributing to the drug's bioavailability. Furthermore, we examined how the gas within the nanobubbles aids in facilitating the drug's translocation through cell membranes. This research contributes to a deeper understanding of the role of CO2 nanobubbles in drug absorption and subsequent release into the bloodstream. The findings suggest that utilizing CO2 nanobubbles could enhance T4 bioavailability and cell permeability, leading to more efficient transport into cells. Additional research opens the possibility of employing lower concentrations of this class of drugs, thereby potentially reducing the associated side effects due to poor absorption.

PSAT364 High-Dose Levothyroxine to Exclude Malabsorption as a Cause of Refractory Hypothyroidism in Hospitalized Patients: Two Cases

Abstract Introduction Levothyroxine malabsorption is one of the causes of refractory hypothyroidism. Administration of a single large dose of levothyroxine can help distinguish this from refractory hypothyroidism due to other causes, but little is known about the utility of this test in patients hospitalized for severe hypothyroidism. Case 1 A 42-year-old woman with Hashimoto's thyroiditis presented with symptomatic hypothyroidism. She reported being compliant with 150 mcg of levothyroxine daily. However, in the past year, her free T4 remained < 0.10 ng/dL on several occasions with TSH > 80 uIU/mL. On admission, free T4 was 0.58 ng/dL, total T4 was 4.9 ug/dL, and TSH was 57.06 uIU/mL. We administered 1000 mcg levothyroxine and found an increase in total T4 at 4 hours (12.1 ug/dL from 4.9 ug/dL). Absorption was found to be 100% at 4 hours implying that she was not taking her levothyroxine appropriately. She was counseled to take levothyroxine at 150 mcg on an empty stomach. At outpatient follow up in 3 weeks, free T4 improved to 1.44 ng/dL and TSH decreased to 1.050 uIU/mL. Case 2 A 42-year-old woman with hypothyroidism, alcohol hepatitis, chronic pancreatitis and previous Roux-en-Y gastric bypass was admitted with progressive lower extremity edema and shortness of breath. She reported taking levothyroxine 175 mcg each morning with her other medications that included omeprazole and magnesium oxide, along with coffee and milk soon after. Her admission labs showed free T4 0.61 ng/dL, total T4 2.8 ug/dL and TSH 84.4 uIU/mL. After 1000 mcg of levothyroxine her total T4 increased from 2.6 ug/dL to 7.8 ug/dL in 4 hours, indicating 100% absorption. The reason for her inadequate outpatient response was probably the combined use of omeprazole, magnesium oxide and coffee with milk, being taken with levothyroxine. She was asked to continue levothyroxine 150 mcg on an empty stomach. Method: Patients were made NPO at midnight prior to the morning of the study. Baseline total T4 was obtained at 6: 00 AM and 1000 mcg of oral Levothyroxine was administered while the patient was monitored on telemetry. Total T4 was measured at 2 and 4 hours after administration. Percentage absorption (% absorbed) = [[Increment TT4 (mcg/dL)×10 (dL/L)]/[total administered LT4 (mcg)]]×Vd (L)X100; Increment TT4 = [Peak TT4] - [Baseline TT4]; Vd (volume of distribution) = 0.442×BMI1 Conclusion These cases indicate that a 1000 mcg T4 absorption study is safe and reasonable to perform in patients who are hospitalized for profound hypothyroidism when outpatient evaluation has been ineffective or challenging. 1 Gonzales KM, Stan MN, Morris JC 3rd, Bernet V, Castro MR. The Levothyroxine Absorption Test: A Four-Year Experience (2015-2018) at The Mayo Clinic. Thyroid. 2019 Dec;29(12): 1734-1742. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Autoinducer-2-mediated quorum-sensing system resists T4 phage infection in Escherichia coli.

In response to the restriction of nutrients and predation by natural enemies, bacteria have evolved complex coping strategies to ensure the reproduction and survival of individual species. Quorum sensing (QS) is involved in the bacterial response to phage predation and regulation of cellular metabolism. However, to date, no clear evidence exists regarding the involvement of autoinducer-2 (AI-2)-mediated QS systems in Escherichia coli in response to the challenges of nutrient restriction and phage infection. In this study, the role of the AI-2-mediated QS system in resisting T4 phage infection and regulating cell mechanisms in E. coli was revealed for the first time. This effect of the AI-2-mediated QS was achieved by simultaneously downregulating the T4 absorption site and carbon and glucose metabolism. Additionally, we found that lsrB, a metabolic brake, participates in AI-2-mediated regulation and maintenance of the normal metabolic balance of cells. The novel phage defense strategy and regulation and maintenance of cellular metabolism effectively limited the expansion of the phage population.

Gastrointestinal Malabsorption of Thyroxine.

Levothyroxine, a largely prescribed drug with a narrow therapeutic index, is often a lifelong treatment. The therapeutic efficacy of T4 may be marred by behavioral, pharmacologic, and pathologic issues acting as interfering factors. Despite a continuous search for an optimal T4 treatment, a significant number of patients fail to show a complete chemical and/or clinical response to this reference dose of T4. Gastrointestinal malabsorption of oral T4 represents an emerging cause of refractory hypothyroidism and may be more frequent than previously reputed. In this review, we examine the pharmacologic features of T4 preparations and their linkage with the intestinal absorption of the hormone. We have stressed the major biochemical and pharmacologic characteristics of T4 and its interaction with the putative transporter at the intestinal level. We have examined the interfering role of nutrients, foods, and drugs on T4 absorption at the gastric and intestinal levels. The impact of gastrointestinal disorders on T4 treatment efficacy has been also analyzed, in keeping with the site of action and the interfering mechanisms. Based on the evidence obtained from the literature, we also propose a schematic diagnostic workup for the most frequent and often hidden gastrointestinal diseases impairing T4 absorption.

Thyroxine softgel capsule in patients with gastric-related T4 malabsorption.

The key role of an intact gastric acid secretion for subsequent intestinal T4 absorption is supported by an increased requirement of thyroxine in patients with gastric disorders. A better pH-related dissolution profile has been described in vitro for softgel T4 preparation than for T4 tablets. Our study was aimed at comparing softgel and tablet T4 requirements in patients with gastric disorders. A total of 37 patients with gastric-related T4 malabsorption were enrolled, but only 31 (28F/3M; median age = 50 years; median T4 dose = 2.04 μg/kg/day) completed the study. All patients were in long-lasting treatment (>2 years) with the same dose of T4 tablets when treatment was switched to a lower dose of softgel T4 capsules (-17 %; p = 0.0002). Assessment of serum FT4 and TSH was carried out at baseline and after 3, 6, 12, and 18 months after the treatment switch. In more than 2/3 of patients (good-responders n = 21), despite the reduced dose of T4, median TSH values were similar at each time point (p = 0.3934) with no change in FT4 levels. In the remaining patients (poor-responders n = 10), TSH levels were significantly higher at each time point than at baseline (p < 0.0001). To note, in five of them intestinal comorbidity was subsequently detected. Comorbidity associated with poor-responders status was the only significant predictor in multivariate analysis (OR = 11.333). Doses of softgel T4 capsules lower than T4 tablet preparation are required to maintain the therapeutic goal in 2/3 of patients with impaired gastric acid secretion.

Oral liquid formulation of levothyroxine is stable in breakfast beverages and may improve thyroid patient compliance.

Patients on treatment with levothyroxine (T4) are informed to take this drug in the morning, at least 30 min before having breakfast. A significant decrease of T4 absorption was reported, in fact, when T4 solid formulations are taken with food or coffee. According to preliminary clinical study reports, administration of T4 oral solution appears to be less sensitive to the effect of breakfast beverages on oral bioavailability. In the present study, stability of T4 oral solution added to breakfast beverages was investigated. A 1 mL ampoule of single-dose Tirosint® oral solution (IBSA Farmaceutici Italia, Lodi, Italy) was poured into defined volumes of milk, tea, coffee, and coffee with milk warmed at 50 °C, as well as in orange juice at room temperature. Samples were sequentially collected up to 20 min and analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The results of the study demonstrated that T4 is stable in all beverages after 20 min incubation. Demonstration of T4 stability is a prerequisite for a thorough evaluation of the effect of breakfast beverages on the bioavailability of T4 given as oral solution and for a better understanding of the reasons underlying a decreased T4 bioavailability administered as solid formulations.

Ciprofloxacin and Rifampin Have Opposite Effects on Levothyroxine Absorption

Levothyroxine (L-T4) absorption varies between individuals, and can be affected by various concomitantly administered drugs. Case reports have indicated an association between cotreatment with ciprofloxacin or rifampin and hypothyroidism in patients on a stable L-T4 dose. The effects of two antibiotics on T4 absorption were prospectively assessed in a double-blind, randomized, crossover fashion. Eight healthy volunteers received 1000 μg L-T4 combined with placebo, ciprofloxacin 750 mg, or rifampin 600 mg as single doses. We measured total plasma thyroxine (T4) concentrations over a 6-hour period after dosing using liquid chromatography-tandem mass spectrometry. For each study arm, areas under the T4 plasma concentration-time curve (T4 AUCs) were compared. Coadministration of ciprofloxacin significantly decreased the T4 AUC by 39% (p = 0.035), while, surprisingly, rifampin significantly increased T4 AUC by 25% (p = 0.003). Intestinal absorption of L-T4 is differentially affected by acute coadministration of ciprofloxacin or rifampin. Mechanistic studies focused on intestinal and possibly hepatic thyroid hormone transporters are required to explain the observed drug interactions with L-T4.

Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches

Although levothyroxine sodium is highly prescribed worldwide, the exact daily dosage, mode of assumption, and refractoriness to treatment are as yet matter of debate. Growing evidence highlighted that undertreatment with T4 has detrimental effects on several tissues and functions. This is even more proper during pregnancy, when an inadequate treatment may increase the likelihood of obstetric complications and may affect the neuropsychological performance during childhood [1]. In adult patients, subclinical hypothyroidism has been reported to be involved in impaired lipid metabolism and atherosclerosis as well as in cardiovascular disorders [2]. The need for an individually tailored dose potently emerges from these findings. Thyroxine treatment should no longer be prescribed according to the commercially available dose size, but rather related to the patient’s weight and age [3]. Two major issues are indeed crucial to obtain an optimal daily dose for a specific patient: an unbiased serum TSH value and an efficient absorption process of thyroxine. The assumption that serum TSH would be a reliable marker of pharmacologic euthyroidism in all tissues has been challenged since its value may be affected by a number of drugs, cosmetics, and pathophysiological conditions [4, 5]. Even the upper limit of normal serum TSH ( or [ 2.5 mU/l) has been questioned [5]. However, it still remains the best available marker, since the direct measurement of thyroxine absorption is not an easy task. Assuming an unbiased serum TSH value in each patient, the absorption process of T4 becomes key for a successful treatment. The daily dose required to obtain the desired TSH value/therapeutic effect is, in fact, not simply a mirror of the ingested dose of thyroxine. One of the major determinants on pharmacological thyroid homeostasis is, thus the incomplete absorption of oral thyroxine (60–80 % of the administered dose) which takes place at the intestinal level. Indeed, the absorbed dose of T4 may be considered the resultant of: (a) patient compliance; (b) some physiological (pregnancy, weight) and/or paraphysiological (behavioral, nutritional) or pharmacological conditions of increased or decreased T4 need; and (c) the presence of diseases which cause malabsorption of T4 (see [6] for review). Repeated failure to reach therapeutic target in response to an ‘‘adjusted’’ dose is a fairly common and frustrating experience. Larger doses of thyroxine are required to attain the desired serum TSH concentrations, leading to expensive and often inappropriate hormonal monitoring. Once attributed to pseudomalabsorption, the increased need for thyroxine may be also explained by an impaired absorption of levothyroxine. Recently, the modality of drug ingestion gained attention. There is now evidence that at least 1 h delay between T4 tablet ingestion and breakfast warrant the best therapeutic achievement [7]. According to Benvenga et al. [8], even the common use of coffee close to the T4 tablet ingestion results in an altered T4 absorption. According to these authors, coffee physically interacts with T4 tablets and retains thyroxine within the intestinal lumen thus making it less available for absorption [8]. This mechanism closely resembles the one suggested for the reduced absorption of thyroxine in patients with celiac sprue [9]. In these patients, the amount of active hormone available for the absorption may be M. Centanni Chief of Endocrinology Unit, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy

A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry

Levothyroxine (T4) is a narrow therapeutic index drug with classic bioequivalence problem between various available products. Dissolution of a drug is a crucial step in its oral absorption and bioavailability. The dissolution of T4 from three commercial solid oral dosage forms: Synthroid ® (SYN), generic levothyroxine sodium by Sandoz Inc. (GEN) and Tirosint ® (TIR) was studied using a sensitive ICP-MS assay. All the three products showed variable and pH-dependent dissolution behaviors. The absence of surfactant from the dissolution media decreased the percent T4 dissolved for all the three products by 26–95% (at 30 min). SYN dissolution showed the most pH dependency, whereas GEN and TIR showed the fastest and highest dissolution, respectively. TIR was the most consistent one, and was minimally affected by pH and/or by the presence of surfactant. Furthermore, dissolution of T4 decreased considerably with increase in the pH, which suggests a possible physical interaction in patients concurrently on T4 and gastric pH altering drugs, such as proton pump inhibitors. Variable dissolution of T4 products can, therefore, impact the oral absorption and bioavailability of T4 and may result in bioequivalence problems between various available products.

HOLOGRAPHIC ANALYSIS OF KIKUCHI ELECTRON DIFFRACTION DATA FROM ${\rm Si}(111)(\sqrt{3}\times\sqrt{3}){\rm R}30^\circ{\rm -Al}$

Holographic analysis was applied to Kikuchi electron diffraction data collected from the [Formula: see text] structure to produce real-space images of the surface structure. Methods for calibrating the initial diffraction data are fully described. The images clearly show features caused by the Al atoms in the T4 absorption site. Measurements of the Al–Si bond length and the height of the Al above the top layer of Si agree with the values known from dynamical LEED studies.

Treatment of primary hypothyroidism during pregnancy: Is there an increase in thyroxine dose requirement in pregnancy?

We studied the dose requirements of thyroxine (T4) and serum concentrations of thyrotropin-stimulating hormone (TSH) and free T4 in 16 pregnant women with primary hypothyroidism due to autoimmune thyroid disease (ATD, n = 11) or thyroidectomy (n = 5). All patients had been advised by their obstetricians to take prenatal vitamins enriched with iron (~90mg/tablet) and calcium (~200 mg/tablet), known to inhibit absorption of T4. We asked patients to take their vitamins 4 hours after ingesting T4 in the morning. The mean T4 dose of 0.10 ± 0.01 (mean ± SEM, mg/d) during pregnancy did not differ significantly from that (0.09 ± 0.005) before or after (0.10 ± 0.01) pregnancy. Similarly, mean serum TSH of 2.7 ± 0.28 mIU/L during pregnancy did not differ significantly from that before (2.2 ± 0.47) or after (3.2 ± 1.31) pregnancy. The mean serum free T4 concentration during pregnancy (16 ± 0.97 pmol/L) was significantly (P <.05) lower than that (22 ± 1.5) before or after (23 ± 2.2) pregnancy and similar to that observed with our free T4 measurement technique in normal (healthy) pregnant women. We next examined the data separately in patients with ATD and thyroidectomy. The mean T4 dose (0.08 ± 0.009) and TSH (2.4 ± 0.29) during pregnancy in 11 ATD patients did not differ appreciably from those before (T4 dose, 0.08 ± 0.0006; TSH, 2.7 ± 0.54) or after (T4 dose 0.09 ± 0.0063; TSH, 4.1 ± 1.91) pregnancy. Similarly, the mean T4 dose (0.12 ± 0.022, n = 5) during pregnancy in thyroidectomized patients was similar to that before (0.12 ± 0.017, n = 3) or after (0.12 ± 0.022) pregnancy. However, serum TSH increased significantly, albeit within the normal range, during pregnancy in thyroidectomized patients (3.2 ± 0.62, n = 5 v 0.41 ± 0.017, n = 3, P <.05) and it (1.3 ± 0.60) decreased significantly (P <.05) after pregnancy. Our data suggest that (1) the dose requirement of T4 does not change systematically in pregnancy in most hypothyroid women. There may occur a modest increase in T4 dose requirement during pregnancy in some thyroidectomized patients; (2) diminished absorption of T4, possibly related to ingestion of exogenous agents (eg, iron, calcium, vitamins), may have contributed to previous suggestions of substantial increased T4 requirement in pregnancy; (3) ingestion of T4 dose absorption-inhibiting agents some 4 hours away from T4 markedly diminishes or obviates their effect in many patients. Although many hypothyroid patients may not require an adjustment in their T4 dose during pregnancy, it is prudent to monitor all such patients carefully as the consequences of inadequate therapy may be very important. Copyright 2003, Elsevier Science (USA). All rights reserved.

The Acute Effect of Calcium Carbonate on the Intestinal Absorption of Levothyroxine

To determine the acute effect of calcium, we measured levothyroxine absorption after ingestion of thyroxine (T4) with and without simultaneous ingestion of calcium (as calcium carbonate) in seven volunteers without thyroid disease. Serum total T4, total triiodothyronine (T3), free T4, and thyrotropin (TSH) levels were measured after ingestion of 1,000 microg of levothyroxine on two separate visits at 4-week intervals: (1) levothyroxine alone and (2) levothyroxine together with 2.0 g of calcium as calcium carbonate. The amount of absorbed levothyroxine was calculated as the incremental rise in serum T4 level during the first 6 hours multiplied by the volume of distribution for the hormone. When 1,000 microg of levothyroxine alone was given to subjects, the maximum average total T4 absorption was 837 microg (83.7% of the dose ingested) at 120 minutes. When levothyroxine was coadministered with 2.0 g of calcium (as calcium carbonate), the maximum average T4 absorption decreased to 579 microg (57.9% of the dose ingested) at 240 minutes. The total levothyroxine absorption over 6 hours was significantly greater with thyroxine than that with thyroxine and calcium (p = 0.02). The administration of calcium and levothyroxine in these subjects was associated with a significant reduction in the peak increment in serum total T4 (p = 0.02) and free T4 levels (p = 0.03), as well as a significant reduction in the overall increment in serum total T4 (p = 0.003), free T4 (p = 0.002), and total T3 levels (p = 0.01) over four time points (120 minutes, 240 minutes, 360 minutes, 1,440 minutes). In summary, this pharmacokinetic study in seven volunteers indicates that calcium carbonate acutely reduces T4 absorption.

Human Thyroxine Absorption: Age Effects and Methodological Analyses

Experience with the use of simultaneous oral and iv radioiodine tracers of thyroxine (T4) to measure T4 absorption was reviewed to determine the effect of advanced age on T4 absorption and to search for acceptable simplifications in the measurement methodology. (1) Age effect: In control subjects, T4 absorption did not differ with age between 21 and 69 years; it averaged 62.8 +/- 13.5% (SD) in subjects over age 70 compared with 69.3 +/- 11.9% in subjects aged 21-69 (p < 0.001). We conclude that, because of this small but significant reduction in T4 absorption efficiency in the elderly, it is especially important to monitor individual response to replacement T4 doses in this age group. (2) Methodology studies: Intrasubject coefficient of variation for T4 absorption in triplicate studies averaged 8.9%, when an identical method was used at weekly intervals (n = 3). When the 3 studies were done by 3 separate methods (sequential po and i.v. 123I-labeled T4, sequential 125I-labeled T4 po and i.v., and simultaneous po and i.v. doses of different tracers), the intrasubject coefficient of variation averaged 9.8% (n = 8). When the absorption calculation used only one serum sample, taken after isotopic equilibrium was achieved at 24 h [the double isotope (eq) method], calculated T4 absorption differed little from that calculated in the same subjects using a full serum time-activity curve and a noncompartmental analysis [the double isotope (AUC) method]. Compared with a compartmental model solution, both methods slightly overestimated T4 absorption. In 4 subjects given i.v. radioiodide as a third tracer at the same time demonstrated that, as long as radioiodide contamination of the T4 tracers is measured and accounted for in the standards, contaminating radioiodide has no clinically significant effect on T4 absorption measurements. When an oral tracer of T4 was considered alone, without an i.v. tracer to correct for T4 metabolism, the estimates of T4 absorption correlated in a curvilinear fashion with T4 absorption as measured by the double isotope method. Except at very low absorption levels, the oral tracer alone is a poor predictor of T4 absorption. We conclude that, when using a double isotope method to measure T4 absorption, it is acceptable to rely on a single serum sample taken at 24 h, a time when isotopic equilibrium between the two tracers has been reached.(ABSTRACT TRUNCATED AT 400 WORDS)

Enterohepatic regulation and metabolism of 3,5,3'-triiodothyronine in hypothyroid rats.

Several steady state indices of thyroid hormone distribution, metabolism, excretion, and absorption were measured in intact hypothyroid and euthyroid rats, to explore the role of intestines and enterohepatic pathways in the dynamic regulation of whole-body thyroid hormone in these two states. Ten rats were studied, 5 normal control (N) and 5 rendered hypothyroid (3.48 vs. 19.8 ng/ml TSH) by surgical thyroidectomy 3.5 weeks earlier (HYPO). High specific activity 125I-labeled T3 (T3*) was infused at the same constant rate for 7 days from osmotic minipumps implanted sc. Daily urine and feces, and seventh-day cardiac and portal venous blood, bile, and whole intestinal contents were assessed. Bowel and feces were homogenized, extracted, and chromatographed, along with serum, bile, and urine samples. Bile, bowel, and fecal extract samples were also hydrolyzed with aryl-sulfatase and/or beta-glucuronidase and chromatographed to identify conjugates and determine total T3* in all fluid and tissue samples. In the N group, the bowel contained 21.2 +/- 1.22 (SD) times more T3* (mass) than plasma (199 ng vs. 9.39 ng), this ratio falling to 9.03 +/- 1.78 in the HYPO group (30.4 ng vs. 3.37 ng), a shift to relatively more T3* in blood. Urinary T3* was zero in both groups. But fecal excretion was 34 +/- 4.43% of total T3* infused (production) in N and only 20.3 +/- 3.05% in HYPO rats, closely paralleling reduced fecal bulk flow, and thus providing more time for T3* absorption. Endogenous T3 and T4 concentrations measured in portal plasma were 15-31% greater in normals and 69-95% greater in HYPO rats than in corresponding systemic plasma samples, a direct indication of absorption of endogenous T3 and T4 in both groups, with greater absorption in the HYPO group. About 66% total T3* was metabolically degraded in N rats, rising to approximately 80% in HYPO rats. Plasma clearance rates of T3 fell more than 50% in HYPO rats, and total T3 production fell to about 20% of normal. It appears that HYPO rats compensate for low T3 by fecally excreting a much smaller fraction of total T3 production, absorbing more T3 and T4, and leaving a larger fraction for T3 action and degradative metabolism.

Sites and patterns of absorption of 3,5,3'-triiodothyronine and thyroxine along rat small and large intestines.

It is clear that some thyroid hormone is absorbed from mammalian intestines, but numerous aspects of this process remain unresolved, including elucidation of the locations, extent and mechanisms of absorption, and the role of absorption in thyroid hormone economy. Our goal was to identify the sites and patterns and estimate rates of absorption of both tracer T4* and T3* comprehensively along the entire length of rat intestines, with normal contents included, to gain further insight into the role of this organ in whole-body thyroid hormone regulation. We measured absorption directly in situ in fed rats, using a variant of the classic intestinal loop technique used by others demonstrating absorption of T4 or of T3 from portions of rat intestines under various conditions. Rats were anesthetized, bile ducts were ligated, and absorption was measured from pylorus to anus, in 14 loops of intestines previously injected with T3* or with T4*, or with T3* and T4* injected in adjacent loops. Rats were maintained under otherwise approximately normal conditions, with intestines in situ and abdomen closed, until killing at 2 h. Excised loop radioactivity was measured and loops were homogenized, extracted, and chromatographed quantitatively to evaluate remaining and absorbed T3* and T4*. Absorption of both T3* and T4* were clearly present and were approximately uniform from all small and large intestinal sections, all containing normal intestinal contents, indicating that the entire organ is involved in whole-body thyroid hormone regulation. Furthermore, T3* and T4* were absorbed at approximately the same rate, adding to evidence reported by others for a simple diffusion absorption mechanism.

Sites and patterns of absorption of 3,5,3'-triiodothyronine and thyroxine along rat small and large intestines

It is clear that some thyroid hormone is absorbed from mammalian intestines, but numerous aspects of this process remain unresolved, including elucidation of the locations, extent and mechanisms of absorption, and the role of absorption in thyroid hormone economy. Our goal was to identify the sites and patterns and estimate rates of absorption of both tracer T4* and T3* comprehensively along the entire length of rat intestines, with normal contents included, to gain further insight into the role of this organ in whole-body thyroid hormone regulation. We measured absorption directly in situ in fed rats, using a variant of the classic intestinal loop technique used by others demonstrating absorption of T4 or of T3 from portions of rat intestines under various conditions. Rats were anesthetized, bile ducts were ligated, and absorption was measured from pylorus to anus, in 14 loops of intestines previously injected with T3* or with T4*, or with T3* and T4* injected in adjacent loops. Rats were maintained under otherwise approximately normal conditions, with intestines in situ and abdomen closed, until killing at 2 h. Excised loop radioactivity was measured and loops were homogenized, extracted, and chromatographed quantitatively to evaluate remaining and absorbed T3* and T4*. Absorption of both T3* and T4* were clearly present and were approximately uniform from all small and large intestinal sections, all containing normal intestinal contents, indicating that the entire organ is involved in whole-body thyroid hormone regulation. Furthermore, T3* and T4* were absorbed at approximately the same rate, adding to evidence reported by others for a simple diffusion absorption mechanism.

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.

The effects of phenytoin (diphenylhydantoin) on the extrathyroidal turnover of thyroxine, 3,5,3'-triiodothyronine, 3,3',5'-triiodothyronine, and 3',5'-diiodothyronine in man.

The extrathyroidal metabolism of T4, T3, rT3, and 3',5'-diiodothyronine (3',5'-T2) was studied before and after treatment with 350 mg phenytoin (DPH) daily for 14 days in six hypothyroid patients receiving constant L-T4 replacement. The total and free serum concentrations of the four iodothyronines were reduced by approximately 30% during DPH treatment, whereas the free fractions in serum were unaltered. Concomitantly, serum TSH increased 137% (P less than 0.02). The production rate (PR) of T4 decreased 16% (P less than 0.005), indicating decreased intestinal absorption (bioavailability) of oral L-T4 during DPH treatment. The fractional rate of 5'-deiodination of T4 to T3 increased from 27% to 31% (P less than 0.05), whereas the rate of 5-deiodination of T4 to rT3 decreased from 45% to 25% (P less than 0.05). The urinary excretion of free and conjugated T4 was 2.3% of the T4 PR and was unaffected by DPH. Thus, the amount of T4 metabolized through nondeiodinative pathways apart from urinary excretion increased from 25% to 44% (P less than 0.05). The apparent distribution volume (Vd) of T4 increased (P less than 0.05), whereas the pool size was unchanged. The PR of T3 did not change during DPH treatment, nor did the mean transit time or the cellular clearance. The rT3 PR was reduced by 54% (P less than 0.02) during DPH treatment. Concomitantly, the transit time increased 10-fold (P less than 0.05), whereas Vd and pool size increased 5-fold (P less than 0.01 and P less than 0.05, respectively). The turnover of 3',5'-T2, in contrast to that of the other iodothyronines, did not change significantly during DPH treatment. T3 formation from T4 was measured in liver microsomal fractions from rats treated for 8 days with DPH and was almost identical to that in untreated animals. The data demonstrate that DPH in therapeutic concentrations did not affect serum protein binding of the iodothyronines. DPH reduced the intestinal absorption of T4 and increased the nondeiodinative metabolism of T4. The resulting decrease in total and free serum T4 and T3 was associated with an increase in serum TSH, demonstrating reduced negative feedback on the pituitary. Our data do not support the assumption that DPH induces increased hepatic deiodinating enzyme activity.(ABSTRACT TRUNCATED AT 400 WORDS)