(Received 5 November 1956) Work with 131I-labelled thyroxine has shown that the plasma thyroxine is

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1 198 J. Physiol. (I957) I36, I98-22 FAECAL CLEARANCE RATE OF ENDOGENOUS THYROID HORMONE IN RATS By N. B. MYANT From the Medical Research Council, Experimental Radiopathology Research Unit, Hammersmith Hospital, London, W. 12 (Received 5 November 1956) Work with 131I-labelled thyroxine has shown that the plasma thyroxine is excreted in the bile (Gross & Leblond, 1947; Albert & Keating, 1952). In rats, the rate of excretion of endogenous thyroid hormone in the bile, expressed as the volume of plasma cleared in unit time, has recently been shown to be about 45 ml. of plasma per day (Myant, 1957). Since the concentration of thyroid hormone in rat's plasma is about 5,ug/1 ml. (Taurog & Chaikoff, 1946), it seems probable that the liver transfers some 2,ug of thyroid hormone from the plasma into the bile each day. This is nearly half the rate at which a normal rat's thyroid makes thyroid hormone (Dempsey & Astwood, 1943). It is, therefore, of some importance to know how much of the biliary iodine is reabsorbed from the intestine under normal conditions. This paper describes an attempt to measure the proportion reabsorbed, from the difference between the biliary and faecal clearance rates of endogenous thyroid hormone labelled by 131I. METHODS Adult rats of the Wistar strain were used. The thyroid hormone in their circulation was labelled with 131I by an intraperitoneal injection of 2,uc of radio-iodide 3 days before measurements of faecal excretion were begun. Each rat was placed in a separate cage from which urine and faeces could be collected separately. From the third day, 5 ml. samples of blood were taken daily by cardiac puncture at the beginning of each collection period. The protein-bound radio-iodine was separated from the plasma by precipitation with trichloroacetic acid. The faecal clearance rate of the plasma thyroid hormone, expressed as the volume of plasma cleared per day, was estimated as Total 1311 in faeces collected over each 24 hr plasma concn. of protein-bound 131I at beginning of collection period' The methods used for measuring the biliary clearance rate of the plasma thyroid hormone (Myant, 1957) and for measurement of the total l3li in the faeces and urine (Myant, 1956) were those described elsewhere.

2 FAECAL EXCRETION OF THYROID HORMONE 199 RESULTS In four rats, daily measurements of the plasma protein-bound 1311 and of faecal 1311 were made for 12 days. The common bile duct was then cannulated and the biliary clearance rate measured over a period of 3 min. After the measurement of the clearance rate was completed, the common bile duct was tied by a silk ligature about 1 cm above the opening into the duodenum, and the rat's abdomen was closed with silk sutures. Measurement of the 1311 in the plasma and faeces was continued for four more days. At the end of this time the rats were deeply jaundiced and their faeces were pale grey. In three other rats the plasma protein-bound 131I and faecal 131I were measured daily for 6 days, but the biliary clearance rate was not measured. TABLE 1. Faecal and biliary clearance rates of endogenous thyroid hormone, expressed as the virtual vol. of plasma cleared/day % reabsorbed. Faecal Biliary Biliary minus Faecal 1 Rat clearance rate* clearance ratet Biliary ± ± ± ± i ±1-8 Av ml./day * Average of all estimates on different days before bile duct ligated. t Estimated from clearance rate measured over 3 min. Fig. 1 shows the observations on one of the four rats, and Fig. 2 shows the faecal clearance rate in the same rat, estimated on each day. The faecal clearance rate in this rat averaged ml., and the biliary clearance rate (calculated from the single estimate) was 32-8 ml. of plasma/day (Fig. 2). The daily amount reabsorbed from the intestines was, therefore, equivalent to 14- ml. of plasma, or 42-6 % of the amount excreted in the bile. In the four rats the faecal clearance rate varied from 12-8 to 32-1 ml./day and the percentage reabsorbed, calculated from the difference between the biliary and faecal clearance rates,varied from 38- to 67-7 (Table 1). In all seven rats the faecal clearance rate averaged 19-5 ml. of plasma/day. After the bile duct was tied, the faecal clearance rate fell markedly, but the fall was followed in every rat by a rise to 1-2 % of the control value within 3 or 4 days (Fig. 2).

3 2 N. B. MYANT IE 5 ) x'- F 3 ( - L *o _ - _ L 4' _ c 2 '1OII- ) E E I I A a I a a Days A a ai t Fig. 1. Rat 1. Plasma protein-bound l31i conen. () and faecal excretion of 13IJ ( ) before and after ligation of common bile duct (shown by arrow). -n 3 ' 2 C 4) -;; 1 Li~ - D D D D ) D D I I I I I I In Days Fig. 2. Rat 1. Faecal clearance rate of endogenous thyroid hormone (() before and after ligation of common bile duct (shown by arrow), with single estimate of biliary clearance rate (-). I

FAECAL EXCRETION OF THYROID HORMONE 21 DISCUSSION Since the time taken for the biliary 1311 to travel from the duodenum to the faeces is not known, the expression used here for estimating the faecal

4 FAECAL EXCRETION OF THYROID HORMONE 21 DISCUSSION Since the time taken for the biliary 1311 to travel from the duodenum to the faeces is not known, the expression used here for estimating the faecal clearance rate must be regarded as an approximation. If the lag were much longer than 24 hr, the faecal clearance rate would be overestimated, since the concentration of protein-bound 1311 in the plasma, when the 131I in the faecal sample was secreted in the bile, would be higher than the value chosen, i.e. the denominator chosen may be too low. However, after the third or fourth day of measurements this source of error can be ignored, since the plasma concentration was changing very slowly at this time (Fig. 1). The estimate of the daily clearance of the plasma thyroid hormone into the bile is based on the assumption that the biliary clearance rate of endogenous hormone is constant throughout the day and night, and that the daily rate can, therefore, be estimated from a single measurement made over a short period. Although the biliary clearance rate has not been measured at different times during the whole 24 hr, numerous estimates at different times during the day in different rats, made in connexion with some other work (Myant, 1957), have never revealed any differences correlated with the time of day. Owing to the effect of the continuous removal of bile on the rate of bile flow, it would not have been justifiable to measure the biliary clearance rate over a longer interval. When these approximations have been allowed for, it seems fair to take 19-5 ml./day (Table 1) as an estimate of the faecal clearance rate. The biliary clearance rate of endogenous thyroid hormone has been shown to average 1-86 ml./hr, or 44-6 ml./day, in normal rats (Myant, 1957). These two estimates give a value of 56% for the proportion of the biliary iodine that is reabsorbed from the intestines. This is in satisfactory agreement with the percentage reabsorbed in the four rats in which the biliary and faecal clearance rates were measured. The faecal excretion of at least a third of the biliary 131I may be explained by the conjugation of some of the biliary thyroxine with glucuronic acid (Taurog, Briggs & Chaikoff, 1952), since thyroxine glucuronide has been shown to be poorly absorbed (Briggs, Taurog & Chaikoff, 1953). The reappearance of 1311 in the faeces a day or so after the bile duct is ligated agrees with the observations of Albert & Keating (1952), who found that some 131I was excreted in the faeces when radio-active thyroxine was injected intravenously into rats in which the bile duct was ligated. It is unlikely to be due to the opening up of accessory channels for the bile, because the faeces, examined by naked eye, did not appear to contain bile pigment. It seems more likely that some thyroxine is excreted directly through the wall of the intestine when the bile duct is tied.

22 N. B. MYANT SUMMARY 1. The biliary and faecal clearance rates of endogenous thyroid hormone labelled by 1311 were measured in rats. 2. In seven rats the faecal clearance rate averaged 19-5 ml.

5 22 N. B. MYANT SUMMARY 1. The biliary and faecal clearance rates of endogenous thyroid hormone labelled by 1311 were measured in rats. 2. In seven rats the faecal clearance rate averaged 19-5 ml. plasma/day. 3. As judged from the difference between the biliary and faecal clearance rates, between 38 and 68% of the biliary 131I derived from the circulating endogenous thyroid hormone is reabsorbed from the intestine. REFERENCES ALBERT, A. & KEATIG, F. R. (1952). The role of the gastrointestinal tract, including liver, in the metabolism of radiothyroxine. Endocrinology, 57, BRIGGs, F. N., TAUROG, A. & CHAIKOFF, I. L. (1953). The enterohepatic circulation of thyroxine in the rat. Endocrinology, 52, DEMPSEY, E. W. & ASTWOOD, E. B. (1943). Determination of the rate of thyroid hormone secretion at various environmental temperatures. Endocrinology, 32, GROSS, J. & LEBLOND, C. P. (1947). Distribution of a large dose of thyroxine labeled with radioiodine in the organs and tissues of the rat. J. biol. Chem. 171, MYANT, N. B. (1956). Metabolism and distribution of endogenous thyroid hormone in rats with and without salivary glands. J. Phy8iol. 133, MYANT, N. B. (1957). Relation between the biliary clearance rate of thyroxine and the binding of thyroxine by the serum proteins. J. Physiol. 135, TAUROG, A., BRIGGS, F. N. & CHEIKOFF, I. L. (1952). 131I labelled L-thyroxine. II. Nature of the excretion product in bile. J. biol. Chem. 194, TAUROG, A. & CHAIKOFF, I. L. (1946). On the determination of plasma iodine. J. biol. Chem. 163,

(Roche, Michel & Tata, 1954). Bilirubin is excreted by rats as the glucuronide (Lathe & Walker, 1958). This similarity in the mode of excretion

(Roche, Michel & Tata, 1954). Bilirubin is excreted by rats as the glucuronide (Lathe & Walker, 1958). This similarity in the mode of excretion 16 J. Phy8iol. (1962), 163, pp. 16-167 With 4 text-figure8 Printed in Great Britain THE EFFET OF BLRUBN ON THE EXRETON OF THYROXNE N THE BLE OF RATS BY A. UAR6N*, N. B. MYANT AND. OSORO From the Medical