Replacement Dose, Metabolism, and Bioavailability of Levothyroxine in the Treatment of Hypothyroidism

Lisa H. Fish, Harold L. Schwartz, John Cavanaugh, Michael W. Steffes, John P. Bantle, Jack H. Oppenheimer

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272 Scopus citations


A change in the formulation of the levothyroxine preparation Synthroid (Flint) in 1982 prompted us to reevaluate the replacement dose of this drug in 19 patients with hypothyroidism. The dose was titrated monthly until thyrotropin levels became normal. The mean replacement dose (±SD) was 112±19 μg per day, significantly less (P<0.001) than the dose of an earlier formulation—169±66 μg per day — used in a similar study (Stock JM, et al. N Engl J Med 1974; 290:529–33). The fractional gastrointestinal absorption of a tablet of the current formulation is 81 percent, considerably higher than the earlier estimate of 48 percent. Using high-performance liquid Chromatographic analysis, we found that the current tablet contains the amount of thyroxine stated by the manufacturer. By measuring the bioavailability of the earlier type of tablet in five patients, we inferred that the strength of the previous tablet had been overestimated. In the present study, the thyrotropin levels of patients on replacement therapy returned to normal when serum triiodothyronine concentrations were not significantly different from those of controls (122 vs. 115 ng per deciliter [1.87 vs. 1.77 nmol per liter]), but when serum thyroxine levels were significantly above those of controls (11.3 vs. 8.7 μg per deciliter [145 vs. 112 nmol per liter], P<0.001). These findings suggest the possibility that in humans, serum triiodothyronine may play a more important part than serum thyroxine in regulating the serum thyrotropin concentration. (N Engl J Med 1987; 316:764–70.), THE reformulation in 1982 of a form of levothyroxine, Synthroid (manufactured as tablets by Flint, Inc., Deerfield, Ill.), raised considerable concern about the tablet strength and bioavailability of currently available preparations. In 1984 Staffer and Szpunar1 reported that serum thyroxine levels were increased in patients who were taking the new tablet. These authors and Sawin and coworkers2 reported that the tablet strength of the older preparation contained less levothyroxine than indicated by the manufacturer. These findings suggested that the results of our earlier studies designed to assess the replacement dose of levothyroxine3,4 represented an overestimation, and if so, led to…

Original languageEnglish (US)
Pages (from-to)764-770
Number of pages7
JournalNew England Journal of Medicine
Issue number13
StatePublished - Mar 26 1987

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