Pharmacokinetics of Propylthiouracil in Man After a Single Oral Dose DANIEL S. SITAR,1-2 AND DONALD B. HUNNINGHAKE Departments of Pharmacology and Medicine, University of Minnesota, Minneapolis, Minnesota 55455 ABSTRACT. A specific method for the analysis of propylthiouracil by high pressure ion. exchange chromatography is presented. Preliminary pharmacokinetic data in 6 normal subjects following the
P
HARMACODYNAMIC studies in man of the thionamide antithyroid drug, propylthiouracil, have been hampered by the lack of a specific assay of sufficient sensitivity to determine plasma concentrations after a therapeutic dose. The use of radioactive isotopes (1,2) is not feasible for extensive clinical studies, and the colorimetric assay reported (3) is not specific, because metabolites which result from side chain oxidation of the propyl group (2) would be expected to give a positive reaction for the parent drug (3). The dosage regimen of propylthiouracil is controversial (4), and there is little or no information on the basic pharmacokinetics of this drug which would help to resolve this therapeutic dilemma. A specific method for the analysis of propylthiouracil is presented here, along with a basic pharmacokinetic analysis after a single oral dose to human volunteers. With this procedure, nonradioactive commercial formulations of the drug can be utilized. Received June 5, 1974. Supported by USPHS Grant GM 15477'. Send reprint requests to: Donald B. Hunninghake, M.D., Department of Pharmacology, 105 Millard Hall, University of Minnesota, Minneapolis, Minnesota 55455. 1 Holder of a Medical Research Council of Canada Fellowship. 2 Present address, Division of Clinical Pharmacology, Montreal General Hospital, Montreal, Quebec, Canada.
administration of 200 mg per os of propylthiouracil indicated a half-life of 1.1 hr. (/ Clin Endocrinol Metab 40: 26, 1975)
Materials and Methods Six normal adult volunteers who had been informed of the nature and purpose of the study consented to participate. After an overnight fast of 12 hr, an oral dose of 200 mg of propylthiouracil (4-50 mg tablets; Parke-Davis) was administered with 240 cc of water at 8 AM. One of the volunteers was taking Ovulen-21, but no other medication was taken by any of the participants immediately prior to or during the study. Blood samples were obtained by venipuncture in heparinized tubes immediately preceding and at 0.5, 1, 2, 3, 4, and 5 hr after the dose. Propylthiouracil assay. The blood samples were stored on ice, centrifuged to separate the plasma, and analyzed on the day of collection. Five ml of plasma were added to 1.5 g ammonium sulfate in a 40 ml glass centrifuge tube. The tube was shaken and 20 ml of chloroform were added. The samples were extracted by shaking in the cold for 30 min. The tubes were centrifuged to break the emulsion and 15 ml of the choloroform layer were transferred to 50 ml pear flasks. Solvent was removed in vacuo on a Biichi Rotavapor. The residue was dissolved in 0.5 or 1.0 ml of 20 mM sodium borate solution. Aliquots of this solution were subjected to high pressure ion exchange chromatography using an LCS 1000 instrument (Varian Aerograph) equipped with a stainless steel column (0.125 in x 6 ft) packed with Pellionex SAX anion exchange resin (Reeve Angel). The column temperature was 40 C. The detector was a fixed wavelength ultraviolet photometer set at 254 nm. Operating pressure was 200-350 psi and eluant flow rate was 20 ml/hr. The eluting 26
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PROPYLTHIOURACIL PHARMACOKINETICS solvent was 10 mM sodium borate and 5 mM sodium nitrate solution. Calibration curves were constructed from data derived by addition of known quantities of propylthiouracil to plasma samples which were subjected to the same extraction and analytical procedure as described for the samples from human volunteers. Quantitation was accomplished by peak height analysis. All chemicals utilized in this study were at least reagent grade.
27
1.2 PROPYLTHIOURACIL y=-O.O22+O.I25x
S.E.yx= 10.013 r=0.999
0.8
0.4
Results Figure 1 demonstrates the elution profile of the chloroform extracts of plasma from high pressure anion exchange chromatographic analysis. The plasma blank elution showed no interfering peaks in the region of propylthiouracil elution. The standard and experimental samples were found to coincide exactly for the elution of propylthiouracil. The lower limit of detection was found to be 0.2 /xg/ml. No interference with the assay has been encountered in the presence of the following drugs: propranolol, diazepam, oral contraceptives, chlorothiazide, spironolactone, digoxin, L-thyroxine,
0.024
PROPYLTHIOURACIL Blonk -i Blank Standard ^2
P
HARMACODYNAMIC studies in man of the thionamide antithyroid drug, propylthiouracil, have been hampered by the lack of a specific assay of sufficient sensitivity to determine plasma concentrations after a therapeutic dose. The use of radioactive isotopes (1,2) is not feasible for extensive clinical studies, and the colorimetric assay reported (3) is not specific, because metabolites which result from side chain oxidation of the propyl group (2) would be expected to give a positive reaction for the parent drug (3). The dosage regimen of propylthiouracil is controversial (4), and there is little or no information on the basic pharmacokinetics of this drug which would help to resolve this therapeutic dilemma. A specific method for the analysis of propylthiouracil is presented here, along with a basic pharmacokinetic analysis after a single oral dose to human volunteers. With this procedure, nonradioactive commercial formulations of the drug can be utilized. Received June 5, 1974. Supported by USPHS Grant GM 15477'. Send reprint requests to: Donald B. Hunninghake, M.D., Department of Pharmacology, 105 Millard Hall, University of Minnesota, Minneapolis, Minnesota 55455. 1 Holder of a Medical Research Council of Canada Fellowship. 2 Present address, Division of Clinical Pharmacology, Montreal General Hospital, Montreal, Quebec, Canada.
administration of 200 mg per os of propylthiouracil indicated a half-life of 1.1 hr. (/ Clin Endocrinol Metab 40: 26, 1975)
Materials and Methods Six normal adult volunteers who had been informed of the nature and purpose of the study consented to participate. After an overnight fast of 12 hr, an oral dose of 200 mg of propylthiouracil (4-50 mg tablets; Parke-Davis) was administered with 240 cc of water at 8 AM. One of the volunteers was taking Ovulen-21, but no other medication was taken by any of the participants immediately prior to or during the study. Blood samples were obtained by venipuncture in heparinized tubes immediately preceding and at 0.5, 1, 2, 3, 4, and 5 hr after the dose. Propylthiouracil assay. The blood samples were stored on ice, centrifuged to separate the plasma, and analyzed on the day of collection. Five ml of plasma were added to 1.5 g ammonium sulfate in a 40 ml glass centrifuge tube. The tube was shaken and 20 ml of chloroform were added. The samples were extracted by shaking in the cold for 30 min. The tubes were centrifuged to break the emulsion and 15 ml of the choloroform layer were transferred to 50 ml pear flasks. Solvent was removed in vacuo on a Biichi Rotavapor. The residue was dissolved in 0.5 or 1.0 ml of 20 mM sodium borate solution. Aliquots of this solution were subjected to high pressure ion exchange chromatography using an LCS 1000 instrument (Varian Aerograph) equipped with a stainless steel column (0.125 in x 6 ft) packed with Pellionex SAX anion exchange resin (Reeve Angel). The column temperature was 40 C. The detector was a fixed wavelength ultraviolet photometer set at 254 nm. Operating pressure was 200-350 psi and eluant flow rate was 20 ml/hr. The eluting 26
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 07 July 2015. at 16:26 For personal use only. No other uses without permission. . All rights reserved.
PROPYLTHIOURACIL PHARMACOKINETICS solvent was 10 mM sodium borate and 5 mM sodium nitrate solution. Calibration curves were constructed from data derived by addition of known quantities of propylthiouracil to plasma samples which were subjected to the same extraction and analytical procedure as described for the samples from human volunteers. Quantitation was accomplished by peak height analysis. All chemicals utilized in this study were at least reagent grade.
27
1.2 PROPYLTHIOURACIL y=-O.O22+O.I25x
S.E.yx= 10.013 r=0.999
0.8
0.4
Results Figure 1 demonstrates the elution profile of the chloroform extracts of plasma from high pressure anion exchange chromatographic analysis. The plasma blank elution showed no interfering peaks in the region of propylthiouracil elution. The standard and experimental samples were found to coincide exactly for the elution of propylthiouracil. The lower limit of detection was found to be 0.2 /xg/ml. No interference with the assay has been encountered in the presence of the following drugs: propranolol, diazepam, oral contraceptives, chlorothiazide, spironolactone, digoxin, L-thyroxine,
0.024
PROPYLTHIOURACIL Blonk -i Blank Standard ^2
