ActaMed Scand 201:4144, 1977

Bioavailability of Propylthiouracil: Interindividual Variation and Influence of Food Intake

A. Melander, E. WAhlin, K. Danielson and A. Hanson

From the Department of Clinical Pharmacology, Division of Toxicology, the Department of Clinical Chemistry (Malmo General Hospital), University of Lund, Lund, and the Unit of Community Care Sciences,

Dalby , Sweden

ABSTRACT. The bioavailability of 6-propylthiou1-a- cil (PTU) has been examined in eight healthy volunteers, with respect to interindividual variation and influence of food intake. PTU was given as a single oral dose, both in a fasting state and together with a standardized breakfast. Numerous venous blood samples were taken during 5 hours after PTU ingestion, and the concentration of unmetabolized PTU in serum was determined by a specific gas- chromatographic technique. The observations indi- cate that the amount of PTU absorbed is subject to a large interindividual variation, and that concomitant food intake may exert a minor and non-systematic influence on PTU absorption. Hence, the major issue in PTU therapy is the individualization of the size and interval of dosage. Testing of single-dose PTU ki- netics in patients would apparently be helpful.

The vast majority of drugs are administered orally, and many drugs are taken three or even more times per day. With this schedule, the drug is liable to be ingested close to meals. However, there is little information as to the influence of a meal on the gastrointestinal absorption of drugs. Therefore, we have initiated a series of studies concerning the influence of concomitant food intake on the bioavailability of different drugs. In these studies, we have observed that the influence of food intake sometimes can be drastic and have consequences for therapy routines (4).

Propylthiouracil (PTU), methimazole and car- bimazole are thyrostatic drugs, i.e. they inhibit synthesis of thyroid hormones within the thyroid gland. 6-PTU, in addition, reduces the extrathy- roidal conversion of thyroxine (T,) to the more active 3,5,3'-triiodothyronine (T,) and enhances the

formation of the metabolically inactive 3,3',5'-tri- iodothyronine (reverse TS, rT3) (9). As this effect is rapid, while the thyrostatic effect does not lead to major reductions of the serum levels of T3 until the thyroid hormone stores are depleted, PTU may of- fer a therapeutic advantage. In several countries, however, carbimazole or methimazole, rather than PTU, is the predominant drug in the treatment of hyperthyroidism, because these two drugs are held to be more efficient than PTU. Furthermore, the risk of therapy failure is apparent, as PTU is rapidly eliminated and hence must be administered at short intervals (1, 2, 6, 7). With this frequency, adminis- tration probably occurs close to meals, which might affect the bioavailability of the drug. This possibility has been explored in the present study. In addition, the interindividual variation in PTU bioavailability was estimated.

MATERIAL AND METHODS Eight clinically healthy volunteers, five females and three males, aged 18-36, weight range 55-75 kg, served as test subjects. Routine blood status and conventional liver function tests were normal in all. After total abstention from food and liquid for ten hours (10 p . m . 4 a.m.), a polyethene cannula was inserted into an antebtachial vein, and 10 ml of blood was collected (0 value-blank). There- after, 6-PTU-300 mg in 50 mg tablets, all of the same brand and batch (Tiotil, Pharmacia, Uppsala, Sweden+ was ingested either together with 100 ml of drinking water or immediately after a standardized breakfast. The breakfast, prepared by a dietician, was composed of 150 ml low-fat milk, 100 ml orange juice, 1 egg, 2 pieces of crisp bread, 5 g margarine, 20 g orange marmalade, and 20 g cheese. This equaled 20 g (20%) protein, 17 g (35%) fat and 50 g (45%) carbohydrates and a total energy of 1840 kJ (440 kcal). About 100 ml non-sweetened, black coffee

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42 A . Melander et al.

Table I , Estimates of kinetic parameters ofpropylthiouracil in eight healthy volunteers given a singlr oral dose on an empty stomach and together with a standardized breakfast tlas=observed absorption delay, t,,,=observed time of peak concentration, C,,,=observed peak concentration, t,l2=estimated elimination half-life, AUC=estimated area under the serum concentration curve

Mean Subj. thi? [ma, Cmw. t 112 concentration no. (rnin) (min) (pmol/l) (rnin) AUC (wnol/l)

Fasting 1 30 2 40 3 15 4 55 5 10 6 10 7 50 8 15

150 95 60

120 55 60

I15 65

Non-fasting 1 20 95 2 60 190 3 I5 110 4 55 85 5 20 60 6 30 120 7 20 60 8 15 85 Statistical significance (F-test) of difference:

between fasting and non-fasting

between individuals conditions

17.0 81.1 40.5 32.3 40.5 30.6 23.5 49.4

25.3 45.2 28.8 47.0 27.6 25.9 31.1 48.2

N.S . p<O.OI

55 85 60 75 85 75 60" 95

1 I5 160" 100 80 70

115" 50 85

N.S. p<O.OI

2 310 9 820 5 310 5 260 6 010 5 280 3 100 7 690

3 080 7 870 5 080 6 410 3 430 4 930 3 170 9 310

N.S. p<O.OOI

8.8 37.6 18.8 21.7 20.6 18.2 12.3 27.0

11.2 32.9 17.6 26.4 12.3 18.2 14.7 32.9

N.S. p<O.OOI

Half-life estimate based upon three observations only.

was included. The dietician or the nurse collecting the blood samples surveilled eating and intake of tablets. When the tablets were taken on an empty stomach, the subjects abstained from food and liquid for another two hours after drug administration.

Blood samples (about 10 ml) were drawn before (0 h) and at about 15,30 ,45 ,60 ,75 ,90 , 105, 120, 150, 180,210, 240, and 300 min after drug ingestion. The exact time (adjusted to the nearest minute) of blood sampling (when the sampling tube was half-filled) was recorded and used in calculations and graphs. Before each blood sampling, 1-2 ml blood was obtained and discarded, and after each sampling 2-4 ml0. I5 M saline was injected via the cannu- la. The blood samples were left at room temperature for more than one but less than two hours. They were then centrifuged, and serum was collected and frozen at -20°C until assayed for PTU content. PTU concentration in serum was assessed by a specific gas chromatographic method, recently described by Schuppan et al. (6).

The arithmetic and logarithmic values of the measured serum concentrations were plotted against time in diagrams, from which the time to peak concentrations, elimination half-lives and trapezoidal AUC (area under the serum concentration curve from time of full influx (flag) to 300 min) values were calculated.

Statistical differences were calculated by r-tests.

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RESULTS

As judged from the serum concentration curves, the rate of elimination of PTU from blood appeared to be rapid, the half-life being 1-2 hours. However, due to absorption delays occurring sometimes in the preprandial, sometimes in the postprandial state, adequate determinations of the elimination half- lives could not always be made (Table I , Fig. I ) .

Within most individuals, the preprandial and postprandial curves differed both with respect to absorption rates, peak concentrations, time to peak concentrations and AUC values. However, there was no systematic variation: AUC was reduced postprandially in a few subjects, while the opposite was found in others. In still other individuals, the AUC values were similar, but the times to reach peak concentration differed (Fig. 1, Table I ) .

The variation between individuals was large; in particular, the difference in AUC values was pro- nounced, irrespective of whether pre- or postpran- dial curves were compared (Table I , Fig. I ) .

Bioavailubility of propylthiourucil 43

2 4 Hours

2 4 Hours

Fig. 1 . Serum levels of unmetabolized propylthiouracil (PTLI) in two volunteers after a single oral dose (300 mg) given on a fasting stomach ( - - - ) and together with a standardized breakfast (-). The amounts of PTU absorbed differed greatly (cf. Table I ) between subject 1 (top) and subject 2 (bottom). Food intake appeared to hasten PTU absorption in subject I but to delay absorp- tion in subject 2 (cf. Table I) .

DISCUSSION

Adequate measurements of drug levels in blood presuppose techniques which are sufficiently specific and sensitive. For PTU determinations, various investigators have employed a colorimetric technique that lacks specificity: not only other drugs but also several endogenous substances in- terfere with the assay ( I , 5). Moreover, it is appar- ent that metabolites of PTU can yield reaction products which are indistinguishable from that of the parent compound (8). Indeed, using the same colorimetric technique (9, two different groups have reported highly discrepant half-life values ( 1 , 8). Specific methods have been devised recently (6, 7 ) and one of these, a gas-chromatographic tech-

nique by Schuppan et al. (6) , was adopted for the present study.

Both the specific and the non-specific assays have a rather low sensitivity, as indicated by the finding that serum concentrations of PTU can- not be followed for more than about 4-6 hours after administration of a single oral dose ( 1 , 5-7). It fol- lows that, if absorption is delayed, the plasma half- life determination has to be based on very few serum values. Such delays occurred sometimes in the present study, and hence some of the half-life values given in Table I are only rough estimates, as indicated. Nevertheless, the estimated mean half- life of 85 min agrees very well with values reported in other studies (6, 7 ) . It must be emphasized, on the other hand, that since no method has allowed recording of single-dose blood levels of PTU for more than 4-6 hours (vide supra), there may well be an as yet undetected slow elimination phase of PTU.

As judged from the AUC values, the amounts of PTU absorbed differed greatly between individuals. Indeed, the difference between the two extreme values shown in Fig. 1 was more than 5-fold. This suggests that the degree of PTU absorption is sub- ject to a pronounced interindividual variation. As i t has been suggested that the degree of PTU absorp- tion is more varied in hyperthyroid than in eu- thyroid subjects (3), it is not unlikely that absorp- tion differences may account for part of the well known variation in therapeutic efficacy of PTU.

Another reason for this variation in efficacy could be that food intake alters the bioavailability of PTU. Unquestionably, most individuals displayed PTU concentration curves which differed between the pre- and the postprandial state. Moreover, similar results were obtained when the experiments were repeated in three of the participating subjects (data not shown in Table I). Hence, it is not probable that the recorded differences were purely incidental. On the other hand, there was no systematic variation: in some individuals, food intake appeared to enhance, while in others it seemed to reduce the absorption of PTU.

Thus, there is no unequivocal answer to the ques- tion whether PTU can be ingested with a meal or should be administered on an empty stomach. However, as the interindividual difference in PTU absorption seemed so much greater than the in- traindividual difference related to food intake, the major issue in PTU therapy is not the mode of oral

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44 A . Melander et al.

administration but the individualization of dose size and dosage interval. In this context, testing of single-dose PTU kinetics in the patient would ap- parently be helpful.

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of propylthiouracil. Acta Pharmacol Toxicol 35: 361, 1974.

2. Lazarus, J. H., Marchant, B., Alexander, W. D. & Clark, D. H.: 3s-S-Antithyroid drug concentration and organic binding of iodine in the human thyroid. Clin Endocrinol4: 609, 1975.

3. McMuny, J. F., Jr, Gilliland, P. F., Ratliff, C. R. & Bourland, P. D.: Pharmacodynamics of propyl- thiourcacil in normal and hyperthyroid subjects af- terasingleoraldose. JClinEndocrinol Metab41:362, 1975.

4. Melander, A., Danielson, K., Hanson, A., Jansson, L., Rerup, C., ScherstCn, B., Thulin, T. & Wilhlin, E.:

Reduction of isoniazid bioavailability in normal men by concomitant intake of food. Acta Med Scand 200: 93, 1976.

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6. Schuppan, D., Riegelman, S., v. Lehmann, B., Pilbrant, A. & Becker, C.: Preliminary pharrnacokine- tic studies of propylthiouracil in humans. J Phar- macokinet Biopharm 1: 307, 1973.

7. Sitar, D. S . & Hunninghake, D. B.: Pharrnakokinetics of propylthiouracil in man after a single oral dose. J Clin Endocrinol Metab 40: 26, 1975.

8. Vesell, E. S., Shapiro, J . R., Passananti, G . T., Jor- gensen, H. & Shirely, B. S . : Altered plasma half-lives of antipyrine, propylthiouracil, and methimazole in thyroid dysfunction. Clin Pharmacol Ther 17: 48, 1975.

9. Westgren, U., Melander, A., Wilhlin, E. & Lindgren, J.: Divergent effects of propylthiouracil on 3,5,3’-tri- iodothyronine (T3) and 3,3’,5’-triiodothyronine (rTd serum levels in man. Acta Endocrinol. In press 1976.

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