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Nalini Singh, MD; Pramil N. Singh, PhD; Jerome M. Hershman, MD

JAMA. 2000;283:2822-2825.

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 (T₄) 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 T₄ 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 T₄, total T₄, total triiodothyronine (T₃), 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 T₄ and total T₄ levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T₄ 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 T₄ levels were 118 nmol/L (9.2 µg/dL) at baseline, 111 nmol/L (8.6 µg/dL) during the calcium period, and 120 nmol/L (9.3 µg/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 T₃ levels did not change during the calcium period. The in vitro study of T₄ binding to calcium showed that adsorption of T₄ 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 T₄ absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability.

Author Affiliations: Division of Endocrinology and Metabolism, VA Greater Los Angeles Healthcare System, UCLA School of Medicine, Los Angeles, Calif (Drs N. Singh and Hershman), and Division of Epidemiology, Loma Linda Medical Center, Loma Linda, Calif (Dr P. Singh).

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