Pharmacodynamics of Propylthiouracil in Normal and Hyperthyroid Subjects After a Single Oral Dose JAMES F. McMURRY, JR., PAUL F. GILLILAND, CHARLES R. RATLIFF, AND PHILIP D. BOURLAND Section of Endocrinology, Section of Clinical Chemistry, and Section of Biophysics, Scott and White Clinic, Temple, Texas 76501 PTU. The serum half-life of the drug in normal subjects was 1.65 h. In patients with hyperthyroidism the serum half-life was similar, and it did not change significantly as the euthyroid state was achieved. (J Clin Endocrinol Metab 41: 362, 1975)

ABSTRACT. Serum levels of propylthiouracil were measured in 8 normal persons and in 7 patients with hyperthyroidism after a single, 300 mg, oral dose of 6-n-propyl-2-thiouracil (PTU). The patients with hyperthyroidism were restudied after 3, 6, and 9 weeks of individualized treatment with

P

ROPYLTHIOURACIL is traditionally

utilized in the treatment of hyperthyroidism by initial large doses which are then reduced after the euthyroid state is achieved (1). In this study, the pharmacodynamics of a single, 300 mg oral dose of 6-n-propyl-2-thiouracil (PTU) were measured in normal persons and in patients with hyperthyroidism to determine whether there was a difference in the serum half-life values of this drug in the two groups and if the values changed as the hyperthyroid patients became euthyroid.

measured by the displacement technique (normal values = 4.5 to 12 /xg/100 ml; Res-O-Mat T4, Mallinckrodt, Inc., St. Louis, Missouri, 63147). Results

All 7 of our patients with hyperthyroidism had elevated serum thyroxine levels after 3 weeks of PTU treatment. Three still had elevated thyroxine values at 6 weeks, and one had mild elevation (13.0 /Ag/100 ml) after 9 weeks of treatment. The patient who remained hyperthyroid at 9 weeks had been asked to increase her therapeutic dose of PTU at 6 weeks. In the other patients the Materials and Methods dose of PTU was reduced: at 6 weeks in 2 Eight normal adult volunteers and 7 patients patients, at 9 weeks in 2 patients, at 12 weeks with hyperthyroidism were given a 300 mg oral dose of PTU after informed consent. Blood in 1 patient, and at 6 months in 1 patient. The serum half-life of PTU in our 8 normal specimens, obtained at 0, 0.5,1,1.5, 2, 3, 4, 5, and 6 h after the single, oral dose, were analyzed subjects was 1.65 h. The mean peak concenfor PTU concentration by the colorimetric tration of PTU in the serum was 6.4 /xg/ml method of Ratliff, et al. (2). The 7 patients with at 1 h. The concentration of the drug dehyperthyroidism were restudied in the same creased rapidly during the 1 to 4 h period and manner after 3, 6, and 9 weeks of individua- at a slower rate between 4 and 6 h (Fig. 1). lized treatment with PTU in divided doses of Before treatment, patients with hyper300-800 mg/day. No other drugs were adminis- thyroidism had a mean peak PTU concentered to these patients during the 9-week period. tration of 10.65 /ag/ml in the serum at 1.5 h. All patients were requested to take their last When the hyperthyroid patients were redose of PTU before midnight, then report for testing between 7:30 and 8:30 on the following studied after 3, 6, and 9 weeks of treatmorning. Serum thyroxine concentration was ment, the mean peak serum concentration of PTU more closely approximated that found in the normal subjects. The serum Received March 3, 1975. Reprint requests to: Dr. James F. McMurry, Jr., levels of the drug varied more in the hyperthyroid patients than in the normal subjects. Scott and White Clinic, Temple, Texas 76501. 362

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SERUM PTU LEVELS IN HYPERTHYROIDISM

363

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8 Normal Volunteers Mean Serum PTU + 1 SE

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0.8 0.6 o

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FIG. 1. Mean serum levels of PTU (0 to 6 h after ingestion of a single, 300 mg, oral dose) in 8 normal subjects.

3

4

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FIG. 2. Linear relationship between log serum PTU and time (1.5 to 6 h). The straight line represents pooled data. Results after a single oral dose of PTU in normal subjects and in hyperthyroid patients (studied before and after treatment with PTU) form a common half-life curve.

Differences in absorption in the hyperthyroid patients may account for this greater variation. Table 1 contains serum concentrations obtained for the normals and the thyrotoxic patients. A semilog plot of serum concentration versus collection time (1.5 to 6 h) for both groups shows a linear relationship (Fig. 2). If the regression lines of the groups are parallel, the half-lives of PTU in the serum are equal. An analysis of covariance (3) shows that the hypothesis of equal half-

lives must be accepted, and gives the best statistical estimate of the common halflife of PTU in the serum to be 1.62 h. Discussion We postulated that an alteration in the serum pharmacodynamics of PTU might

TABLE 1. Mean serum concentrations of PTU (/ng/ml) ± SE Thyrotoxic patients Time (h) 0 0.5 1 1.5 2 3 4

5 6

Nnmuil i ^1 \J\ 111CU

subjects 0.0 ± 5.32 ± 6.41 ± 5.86 ± 4.65 ± 2.98 ± 1.45 ± 0.74 ± 0.31 ±

0.0 0.86 0.44 0.37 0.43 0.75 0.39 0.29 0.20

0 weeks 0.75 ± 7.57 ± 7.17 ± 10.65 ± 7.88 ± 4.75 ± 3.29 ± 2.38 ± 1.34 ±

0.49 2.42 1.77 2.96 2.20 0.78 0.80 0.57 0.35

3 weeks 1.72 6.53 8.66 7.66 5.68 4.16 3.44 1.30 0.63

± ± ± ± ± ± ± ± ±

0.67 1.98 2.51 2.03 1.51 1.16 0.87 0.23 0.25

6 weeks 0.18 5.49 8.27 7.60 7.16 4.00 2.55 1.40 0.95

± ± ± ± ± ± ± ± ±

0.11 1.10 2.41 1.83 1.84 1.29 0.84 0.43 0.26

9 weeks 1.23 5.88 7.34 7.37 7.03 4.51 3.30 2.53 1.65

± ± ± ± ± ± ± ± ±

0.81 1.98 1.34 1.38 1.01 1.35 0.89 0.44 0.57

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364

McMURRY, GILLILAND, RATLIFF AND BOURLAND

explain a need for larger amounts of the drug during initial therapy for hyperthyroidism compared to the smaller amounts needed after the euthyroid state is achieved. However, an analysis of covariance did not demonstrate a significant difference in the serum half-life of PTU in the 8 normal subjects and in the 7 patients with hyperthyroidism who were studied during the early phase of treatment. In a recent report by Sitar and Hunninghake (4), serum concentrations of PTU, measured by a new method of high pressure ion exchange chromatography, were very similar to those we found in our controls and patients after single oral doses. The plasma half-life of PTU and methimazole were studied by Alexander et al. (5) in 2 patients. They found the half-life of PTU to be 2.5 h in one and 8.5 h in the other. The latter patient had renal failure and they concluded excretion of the drug was mainly in the urine. Since plasma radioactivity after the administration of 35Slabeled PTU was the only parameter measured, it is conceivable that they observed a longer half-life because the drug was metabolized and the measured radioactivity included metabolites as well as the intact molecule. Chromatography of the urine after 35S-PTU administration demonstrated a single radioactive compound which did not appear to be identical to PTU in that system.

JCE & M • 1975 VoUl • No 2

The absorption of PTU in our hyperthyroid patients may have varied somewhat in degree or time producing a larger variation in serum levels in these patients than in the normal subjects. The study of Alexander et al. (5) showed excellent absorption of PTU and methimazole and only 3% of the administered radioactive counts were found in the feces of a patient given 35 S-labeled methimazole. Because the thiourea drugs are concentrated by thyroid tissue (6) and the serum half-life of PTU is not significantly different in hyperthyroidism, it appears more likely that a decreasing requirement for PTU is related to changes in thyroid response than to the serum pharmacodynamics of the drug. References 1. Astwood, E. B., In Goodman, L. S., and A. Gilman (eds.), The Pharmacologic Basis of Therapeutics, ed. 4, Macmillan Co. New York, 1970, p. 1487. 2. Ratliff, C. R., P. F. Gilliland, and F. F. Hall, Clin Chem 18: 1373, 1972. 3. Wine, R. L., Statistics for Scientists and Engineers, Prentice-Hall, Inc., Englewood Cliffs, N.J., 1964, p. 492. 4. Sitar, D. S., and D. B. Hunninghake, J Clin Endocrinol Metab 40: 26, 1975. 5. Alexander, W. D., E. Evans, A. MacAulay, T. F. Gallagher, Jr., and J. Londono, Br Med J 2: 290, 1969. 6. Marchant, B., W. D. Alexander, J. H. Lazarus, J. Lees, and D. H. Clark, / Clin Endocrinol Metab 34: 847, 1972.

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Pharmacodynamics of propylthiouracil in normal and hyperthyroid subjects after a single oral dose.

Serum levels of propylthiouracil were measured in 8 normal persons and in 7 patients with hyperthyroidism after a single, 300 mg, oral dose of 6-n-pro...
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