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Effect of calcium carbonate on the absorption of levothyroxine

Singh, Nalini·2000·JAMA
DOI 10.1001/jama.283.21.2822
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Abstract

CONTEXT: The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women. OBJECTIVE: To investigate the potential interference of calcium carbonate in the absorption of levothyroxine. DESIGN: Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T(4)) binding to calcium carbonate. SETTING: Veterans Affairs Medical Center in West Los Angeles, Calif. PATIENTS: Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T(4) and thyrotropin values in the normal range before beginning the study. INTERVENTION: Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months. MAIN OUTCOME MEASURES: Levels of free T(4), total T(4), total triiodothyronine (T(3)), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine). RESULTS: Mean free T(4) and total T(4) levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T(4) levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T(4) levels were 118 nmol/L (9.2 microg/dL) at baseline, 111 nmol/L (8.6 microg/dL) during the calcium period, and 120 nmol/L (9.3 microg/dL) after calcium discontinuation (overall P=.03). Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1. 4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T(3) levels did not change during the calcium period. The in vitro study of T(4) binding to calcium showed that adsorption of T(4) to calcium carbonate occurs at acidic pH levels. CONCLUSIONS: This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T(4) absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability. JAMA. 2000;283:2822-2825

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Crossref · 10.1001/jama.283.21.2822

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  • Only two of the medications that alter LT4 absorption have been studied in a cross-over study design of chronic therapy, with two other studies also conducted prospectively.

    “Only two of these medications have been studied in a cross-over study design of chronic therapy (132,145), with two other studies also conducted prospectively (140,143).”

    From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [132]

  • The list of medications that can alter the absorption of LT4 is extensive and includes calcium carbonate, PPIs, bile acid sequestrants (cholestyramine and colesevelam), phosphate binders, ferrous sulfate, aluminum-containing antacids, and sucralfate.

    “The list of medications that can alter the absorption of LT4 is extensive and includes calcium carbonate (132-134), PPIs (135), bile acid sequestrants (cholestyramine and colesevelam) (136,137), phosphate binders (138,139), ferrous sulfate (140,141), aluminum-containing antacids (142,143), and sucralfate (144,145).”

    From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [132]

  • In hypothyroid patients with normal TSH concentrations, taking LT4 with calcium carbonate for several months increased mean serum TSH from 1.6 mIU/L to 2.7 mIU/L, and it returned to 1.4 mIU/L after discontinuation of calcium (132).

    “Hypothyroid patients with normal TSH concentrations were asked to take their LT4 with calcium carbonate for several months. Their serum TSH values increased from a mean of 1.6 mIU/L to 2.7 mIU/L, and returned to 1.4 mIU/L after discontinuation of the calcium (132).”

    From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [132]

  • Singh et al. reported that both acute and chronic ingestions of calcium carbonate can reduce in vitro bioavailability of T4 by binding it in a dose-dependent fashion at medium pH 2.

    “On this ground, Singh et al. (53) reported that both acute and chronic ingestions of calcium carbonate can reduce the in vitro bioavailability of T4 by binding it in a dose-dependent fashion at medium pH 2.”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [53]

  • Direct complexation and chelation play important roles in the malabsorption of LT4 induced by the intake of many drugs, including calcium and iron supplements, aluminum-containing antacids, bile acid sequestrants, and some foods (eg, fiber-rich foods, coffee, and milk).

    “It is widely acknowledged that direct complexation and chelation play important roles in the malabsorption of LT4 induced by the intake of many drugs, including calcium and iron supplements (72, 73), aluminum-containing antacids (74), bile acid sequestrants (75, 76), and some foods (eg, fiber-rich foods, coffee, and milk) (22, 77, 78).”

    From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [73]

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Authors
Singh, N.
Affiliations
VA West Los Angeles Medical Center (US)
Corresponding author
Singh, Nalini
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2000-06-07
Volume
283
Issue
21
Pages
2822
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.283.21.2822
OpenAlex
W2107234914
Cited by
219
References
16
Citations by year
2026: 7 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 4 · 2021: 9 · 2020: 9 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 7 · 2015: 13 · 2014: 7 · 2013: 5 · 2012: 9
FWCI
5.80
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
Keywords
levothyroxine, calcium carbonate, drug interactions, drug absorption, hypothyroidism, free thyroxine, thyroxine binding, thyroid-stimulating hormone, triiodothyronine, postmenopausal women, antithyroid drug therapy, veterans, thyroid function monitoring
MeSH terms
Absorption, Adult, Aged, Biological Availability, Calcium Carbonate, Drug Interactions, Female, Humans, Hypothyroidism, Male, Middle Aged, Prospective Studies, Thyrotropin, Thyroxine, Triiodothyronine, Cohort Studies

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