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This study aimed to elucidate the clinical efficacy and pharmacokinetics of levothyroxine (LT4) suppository, thus, we examined the pharmacokinetics of thyroxine (T4) after the administration of the suppository in thyroidectomized rats and examined dose and the levels of free T4 (FT4) in patients with hypothyroidism receiving suppositories. Thyroidectomized rats were administered with LT4 solution and LT4 suppository (30 µg/kg), and plasma T4 concentrations were measured using LC/MS. The AUC 0-168 of T4 after rectal administration of the LT4 suppository was 64% lower than these values after oral administration. To evaluate clinical effect of LT4 suppository, we enrolled 6 Japanese patients with hypothyroidism (2 men and 4 women; age, 68.2 13.5 years) who were administered LT4 suppository at Kameda Medical Center from 2007 to 2013 in this case series. The FT4 level during the administration of suppositories was significantly lower than that during the administration of tablets (0.657 0.183 ng/dL vs. 1.25 0.51 ng/dL, p 0.034). The FT4/dose ratio for the suppository was significantly 44% lower than that for the tablet (p 0.020). In conclusion, although the bioavailability of LT4 is lower after administration of the suppository than after the oral formulation, it was suggested that T4 levels can be maintained in patients with hypothyroidism by administering LT4 suppositories at a dose 1.8 times higher than that of the tablet. Thus, the administration of LT4 suppository can be an alternative for treatment with oral medication in clinical practice.Key words levothyroxine; suppository; clinical efficacy; pharmacokinetics; hypothyroidism Thyroid hormones are important hormones that regulate protein synthesis and energy metabolism in the body; the thyroid hormone thyroxine (T4) consists of four molecules of iodine and triiodothyronine (T3) consists of three molecules of iodine. The major thyroid hormone synthesized in the thyroid gland is T4. T4 is converted to T3 in the liver and kidneys by removal of 1 of the 4 molecules of iodine.A disease associated with the deficiency of these thyroid hormones is known as hypothyroidism, and patients with this disease have low levels of free T3 (FT3) and free T4 (FT4) and high levels of thyroid-stimulating hormone (TSH). In 90% or more patients, hypothyroidism is caused by chronic autoimmune (Hashimoto's) thyroiditis, which is caused by cell-and antibody-mediated destruction of the thyroid tissue.1) Thyroidectomy, radioiodine treatment, and external radiation therapy are well-known causes of hypothyroidism. Furthermore, hypothyroidism is much more common in women than in men, and a majority of patients with hypothyroidism develop goiter.2)The results of the United States National Health and Nutrition Examination Survey indicated that the incidence of hypothyroidism was 4.6% (0.3% overt and 4.3% subclinical), and the prevalence of hypothyroidism was higher in subjects in the old age groups and in Caucasian and Hispanic subjects. Synthetic levothyroxine (LT4) is widely used for the tre...