XENOBIOTICA, 1972, VOL. 2, NO. 4, 363-375

The Metabolism of Terbutaline in Man

H. TORSTEN NILSSON, KERSTIN PERSSON and KERSTIN TEGNGR Research and Development Department, Biochemical Laboratory, AB Draco,# Lund, Sweden

(Received 16 March 1972)

1. The metabolism of terbutaline has been investigated in man after oral, intravenous and subcutaneous administration of the tritium-labelled drug.

2. Serum levels and excretion rates were followed for 3-4 days after adminis- tration by the three different routes. After oral administration, one-third to one-half of the dose is excreted in the urine whereas after intravenous and subcutaneous administration > 90”/b is eliminated by this route. The remainder is recovered in the faeces.

3. A method for determination of [3H]terbutaline using ion pair extraction has been developed. A quantitative separation of unchanged drug from its metabolite is achieved in the range 1-250 ng/ml urine or serum.

4. After administration of terbutaline by any of the three routes, high voltage electrophoresis and paper chromatography reveal the presence of only one

’ metabolite. Hydrolysis of urine with /3-glucuronidase and/or sulphatase indicates that the major metabolite is a sulphate conjugate of terbutaline.

Introduction Terbutaline ( 1 - [ 3,s -dihydroxyphenyl] -2-tevt. - butylaminoethanol, Bricany l(”))

is a drug with selective F-receptor-stimulating action (Bergman, Persson & Wetterlin, 1969). The pharmacological properties are documented in studies by Persson & Olsson (1970), who show that the compound has afinity pre- dominantly for the tracheal and bronchial muscles, and terbutaline has been used by asthmatics to relieve bronchoconstriction (Arner, 1970 ; Formgren, 1970 a & b ; Dorsch & Ulmer, 1971 ; Legge, Gaddie & Palmer, 1971). Tissue distribution of [3H]terbutaline in mice has been studied by Bodin, et al. (1972).

Metabolic studies in man of other bronchodilators have been reported. Isoprenaline (l-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol) has been studied by Morgan, et al. (1969) who found that the major metabolite in plasma after oral administration was isoprenaline sulphate but was free isoprenaline after intravenous administration. Martin, et al. (1971) found that with an oral dose of [3H]salbutamol (l-(4-hydroxy-3-hydroxymethyl)phenol-2-tevt.-butyl- aminoethanol) about 90% was excreted in the urine and the peak plasma level was observed 1 to 2 hours after administration. These studies deal with drugs which are catechol derivatives while terbutaline is a resorcinol derivative.

As terbutaline has phenolic hydroxy-groups in the 3,s-positions it would not be expected to be metabolized by cathecol-0-methyl transferase and this has been confirmed by Persson & Persson (1972). These authors also demon- strated the resistance of the compound towards monoamine-oxidase, which may be explained by the presence of a substituted amino group in terbutaline.

# Subsidiary to AB Astra, Sweden.

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3 64 H. Torsten Nilsson, et al.

Another possible metabolic pathway for this drug involves conjugation with sulphuric and glucuronic acids, and hydrolysis experiments with sulphatase and F-glucuronidase have therefore been performed.

The purpose of the present work was to investigate the absorption and excretion of terbutaline in man after oral, intravenous and subcutaneous adminis- tration of clinical doses of the tritium-labelled compound. A similar investiga- tion in dog and rat will be published later.

Materials and methods Compounds

[ 3H]Terbutaline ([ 1 - 3€I] 1 - [3,5-dihydroxyphenyl]-2-tert.- butylaminoethanol) hydrobromide (sp. activity of 1.4 mCi/mg) or sulphate (sp. activity of 1.8 mCi/ mg) (see Fig. 1) were synthetized at the Research Laboratories AB Astra, Sodertalje, Sweden. The radiochemical purity of the compounds was checked either by means of t.1.c. or by high voltage electrophoresis. T.1.c. plates of silica gel F,,, (E nlerck AG) were run in the solvent system n-butanol-acetic acid-water (4 : 1 : 5 by vol). Electrophoresis was performed in Tris-buffer as described below. Radioactivity on plates and strips was detected with a radio- chromatogram scanner (Packard model 7200), and only one radioactive spot was detected by either method. The Ri,-value for the radioactivity on the chromatogram was 0.72, the same as for authentic terbutaline, and in electro- phoresis, radioactive and authentic terbutaline travelled the same distance.

T h e presence of exchangeable tritium in the compound was investigated by distillation of an aq. soln. of terbutaline bromide after 0-45 days storage at - 18". Non-labelled terbutaline hydrobromide and sulphate were synthetized at the Organic-chemical Laboratory, AR Draco (Wetterlin & Svensson, 1968).

Less than 20$ of the tritium was found in the distillate.

Fig. 1. [3H]Terbutaline.

Human studies? Two healthy male subjects received orally 2.8 mCi (17.4pmol) of terbuta-

line, equiv. to 52pglkg body wt. for JB (age 46) and 58pgikg body wt. for H P (age 41). In a second oral study, 6 months later, J B was given 1-6 mCi in 17pmol terbutaline corresponding to 51 pg/kg body wt. The drug was administered as [3H]terbutaline hydrobromide. A third male subject, CGP (age 28) was given 2.9 mCi in 18.0 pmol terbutaline corresponding to 62 pg/kg body wt., the drug being administered as [3H]terbutaline sulphate. The

t T h e absorbed dose of radiation from [3H]terbutaline was calculated according to ICRP publ. 10 (1968) and based upon excretion data obtained in dog experiments. The human investi- gation was permitted by the Isotopic Committee at the University Hospital of Lund, Lund, Sweden.

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The Metabolism of Terbutaline in M a n 3 65

compounds, dissolved in saline, were administered in a hard gelatine capsule after 10 h fasting. After dosing, the subjects were allowed to eat and drink without restrictions.

After an interval of about 4 weeks, JB and HP each received 0.36 mCi in 0.83 pmol terbutaline intravenously (corresponding to 2.5 pg/kg and 2-7 pg/kg body wt. respectively). The drug was administered as [3H]terbutaline hydro- bromide. The third subject, CGP, received intravenously 0.44 mCi in 0.90pmol terbutaline, corresponding to 3.4 pg/kg body wt. In this case, r3H]terbutaline sulphate was used. The compounds were dissolved in 0.5 ml saline, pH 3.5 and given after 10 h fasting. After dosing, the subjects were allowed to eat and drink without restrictions.

Two healthy subjects, BO and SM (age 33 and 27, respectively), both weigh- ing 72 kg, were each given one single subcutaneous injection of 0-25 mg [3H]- terbutaline sulphate corresponding to 0.3 mCi in 0.5 ml saline (pH 3.5). The drug was administered in the morning after fasting for 10 h. One hour after dosing the subjects were allowed to eat.

Urine and faeces were sampled in periods ending as indicated in Figs. 6, 7, 8 and Table 2. All samples were frozen as soon as possible and stored at -20" until assayed.

Blood samples were withdrawn and serum was prepared.

Electrophoresis High voltage electrophoresis of serum and urine was performed in Tris-bufler

(0.1 M, pH 8.5, 64 Vjcm, 90 min) on Whatman paper no. 1 using an apparatus described by Persson & Persson (1972). The electropherograms were examined with a recording radiochromatogram scanner (Packard 7200). Two distinct peaks were obtained, one of them identical with authentic terbutaline. A typical electrophoretic pattern is shown in Fig. 2 (A).

Chromat ograp hy Descending paper chromatography on Whatman no. 1 in the solvent system

of n-butanol-acetic acid-water (4 : 1 : 1 by vol.) was employed in selected experiments to verify the presence of only one metabolite. The R, values (terbutaline 0.74, metabolite 0.43) were determined with the aid of a chromato- gram scanner.

Enzyme hydrolysis Aliquots of urine were incubated with the enzymes P-glucuronidase and

sulphatase. P-Glucuronidase from bovine liver or from E. coli and arylsulphatase from limpets were obtained from Sigma Chemical Company, Helicase, a mixture of P-glucuronidase and sulphatase from Helix Pomatia, was obtained from L'Industrie Biologique Francaise S.A. Enzyme activity was determined by standard spectrophotometric methods according to Sigma Technical Bulletins. The P-glucuronidase preparations were controlled so as not to contain any detectable sulphatase activity. The P-glucuronidase activity in the arylsulpha- tase preparation is given by Sigma to be less than 0.1 unit/mg/h and this was confirmed. It was found that urine completely inhibits the action of the arylsulphatase from limpets but inhibits to a lesser degree the sulphatase in the helicase preparation. In order to eliminate this inhibition, the urine was

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366 H . Torsten Nilsson, et al.

treated at pH 11.5 with BaCl, (0.2 M final concn.) to precipitate inhibiting sulphate and phosphate ions (Dodgson and Spencer, 1953). The enzyme experiments were performed at 37" for 1-4 days and for comparison, incubation without enzyme was also carried out. Aliquots (25-30 1.1) of the incubates (see Table 1) were anaylsed by electrophoresis and paper chromatography as described above (see Fig. 2).

Table 1. Hydrolysis of urine with various enzyme preparations

Enzyme Units added per sample' Buffer

fl-Glucuronidase (bacterial)

fl-Glucuronidase (bovine liver)

Arylsulphatase (limpets)

80 or 320 0.2 M phosphate buffer pH 6.8 (100 pl)

0.2 M acetate buffer pH 5.0 (100 pl)

0.2 M acetate buffer pH 5.0 (100 pl)

1200 or 2400

1150 or 11 500

7800 or 15 600 0.2 M acetate buffer rsulphatase

+ 600 or 1200 p H 5.0 (100 pl) I 8-glucuronidase

Helicase (Helix Pomatia)

Urine (100 1.1) was incubated with enzyme in a total vol. of 200 pl. * One unit of 8-glucuronidase liberates 1 pg phenolphthalein from phenolphthalein

One unit of sulphatase hydrolyses 1 pg of glucuronide in 1 h at 37" and pH 6.8 or 5.0. nitrocatechol sulphate in 1 h at 37" and pH 5.0.

Ion pair extraction The quantitative analysis of unchanged terbutaline in serum and urine was

performed by ion pair extraction (Modin & Schill, 1967). Since the pk, values of terbutaline are 8.8, 10.1 and 11.2, the compound bis-(2-ethylhexyl)-phosphoric acid (Fluka) with pK, 3.2 (Temple & Gillespie, 1966) was a suitable counter ion. T o be able to separate terbutaline and its metabolite in the very low concn. present in serum, it was necessary to use partition chromatography with Celite 545 (Kebo, washed in perchloric acid and methylene chloride) as support (Levine & Doyle, 1967). The ion pair was eluted with methylene chloride containing 0.5 yo bis-(2-ethylhexyl)-phosphoric acid. To improve the separation of terbutaline and its metabolite, a small amount of Celite 545 was placed at the bottom of the column before the support, mixed with the sample, was added. With this technique the pH range 5-8 was examined. At p H 6.5, terbutaline was quantitatively extracted and completely separated from its metabolite. I t is possible to analyse volumes between 0-20-4.00 ml by changing the amounts of the chemicals proportionally and changing the diameter of the column between 10-26 mm.

For analysis of unchanged [3H]terbutaline in serum, 2.00 ml serum was pptd. with 1.00 ml 10% wjv perchloric acid and centrifuged. A 2.00 ml portion of the supernatant liquid was adjusted to pH 6.5 with 0.30 ml 1.8 M-sodium phosphate buffer, pH 6.5 and 0.22 ml 5.0 M-NaOH. Celite 545 (1.0 g), moistened with 0.7 ml methylene chloride and 0.3 ml water, was packed

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The Metabolism of Terbutaline in Man 3 67

at the bottom of a column. Celite (3.75 g), moistened with 5 ml methylene chloride, was added to the buffered serum. After stirring, another 3.75 g dry Celite was added and the mixture was then transferred to the column. The beaker and funnel were rinsed with 2 x 0.2 g dry Celite and the ion pair was then eluted.

Fig. 2. Radiochromatograms of electrophoresis of urine after oral administration of [ 3 H ] terbutaline to man. [3H]Terbutaline sulphate (5 mg) was administered; urine was collected from 0-6 h ; enzyme incubations were for 2 days. (A) untreated urine or urine incubated without enzyme; (C) urine incubated with arylsulphatase ; (D) urine incubated with Helicase, a mixture of 13-glucuronidase and sulphatase.

(B) urine incubated with /3-glucuronidase ;

For analysis of unchanged [3H]terbutaline in urine, 500 p1 urine was buffered with 100p1 1.8 M-sodium phosphate buffer pH 6.5 and subjected to ion pair extraction. Celite 545 (0.5 g), moistened with 0.4 ml methylene chloride and 0-15 ml water, was packed at the bottom of a column. Celite, 0.9 g moistened with 1-2 ml methylene chloride, was added to the buffered urine. After stirring, another 0.9 g dry Celite was added. The homogeneous sample was packed into the column and, after rinsing the beaker and funnel, the elution was carried out.

The initial 4-7 ml of the eluates were collected in a polyethylene vial and dried by heating in a Mic Var Isomantle (Kebo) under H,. Scintillator soln. (15 ml) containing napthalene 100 g/l (BDH), PPO 7 g / l (Arapahoe), dimethyl POPOP 0.3 g,’l (Arapahoe) and dioxane 1 litre (Fisher) was added to the vial. Measurement of radioactivity was performed in a liquid scintillation counter (Coru:Matic 100, Tracerlab and Tri Carb 3320, Packard) and 10 000 counts

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368 H . Torsten Nilsson, et al.

were registered which correspond to a relative standard deviation of 1%. The counting eficiency of 30-40°/, was determined by channels ratio or external standard. Studies with known amounts of [3H]terbutaline (sp. activity 1.4 mCi/mg) at concn. in the range 1-250 ng/ml urine or serum gave 96.1 0.7",, recoveries (mean value & S.E.M., n= 15).

The identity of the eluted compound was determined by electrophoresis after extraction of the dry eluate into 0.1 M-HCI. Only one radioactive peak corresponding to reference terbutaline was detected. After prolonged elution, the presence of the metabolite could be demonstrated. Upon electrophoresis this latter migrated as peak I in the electropherogram of untreated urine, Fig. 2 A.

Determination of total radioactivity For determination of unchanged and conjugated terbutaline, 0.2 ml serum

was dissolved in 2 ml NCS Solubilizer (Nuclear Chicago) at room temp. After 15 min, the scintillator soln. (15 ml of PPO 4 g,'l, dimethyl POPOP 0.05 g,l, toluene 1 litre) was added. The vials were left overnight for adaptation to darkness before counting in the liquid scintillation counter.

For determination of terbutaline and its metabolite in urine, 1 vol. of urine was diluted with 9 vol. water. An aliquot (100-2004) of the diluted urine was added to 15 ml of the dioxane-naphthalene scintillator soln. and counted in the liquid scintillation counter.

For determination of total radioactivity in faeces, one part was diluted with three parts of water and thoroughly mixed with an Ultra-Turrax (Janke & Kunkel). An aliquot, 1-2 g, of the homogenate was applied to an unglazed porcelain boat. The sample was exposed to heat in a quartz-glass tube (length 60 cm, diam. 5-7 cm) placed in an oven (Heraeus RoK 60). The tube had a cone through which the boat was inserted and in addition contained CuO to a length of 25 cm. The adapter was connected via a gas flow meter to an 0, tube. Oxygen was then blown over the boat at a rate of 325 mlimin. The heat was raised slowly and finally kept at 700" for about 20 min. The 3H,0 formed was collected in a tube, chilled in a vessel containing solid CO, and ethanol ( - 80"). When the heating process was finished, 200-300p.1 of the labelled water was counted in 15 ml dioxane-naphthalene scintillator solution. The recovery from faeces was 95.0 f 0*6(y0 (mean value f S.E.M., n = 8).

All radioactive measurements were carried out in this way.

Results and discussion The change in concentration of serum radioactivity over 72 h after oral

administration of [3H]terb~taline is shown in Fig. 3. The peak serum level of both free and conjugated drug is obtained 1-3 h after administration. Unchanged terbutaline ranges from 3.1 to 6.2 ng/ml at the maximum level, which means that about 15% of the drug present is in the free form. Two of the studies show a biphasic curve; one (JB I), has a second maximum about 6 h after administration. In the oral study (JB I), the excretion pattern regarding the amounts present in urine and faeces is the reverse of that found in the remaining three studies (JB 11, H P and CGP) (see Table 2). In the second oral study of subject JB (JB II), only one peak is found and, furthermore, no sign of biphasic curves are seen after intravenous or subcutaneous administration (see

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The Metabolism of Terbutalzne in Man 369

Time af ter dosage (hour)

Fig. 3. Serum concentration of total radioactivity and unchanged terbutaline after oral administration of [ 3H]terbutaline to man. [3H]Terbutaline hydrobromide or sulphate (5 mg) was administered. Total radioactivity is expressed as terbutaline. Total radioactivity: 0 - - - 0 JB I, n---n JB 11, --- HP, 0 --- 0 CGP. Unchanged terbutaline: 0- JB I, fi-a JB 11, A------A HP, m-H CGP.

Table 2. Recovery of radioactivity after a single oral, intravenous or subcutaneous dose of [3H]terbutaline to male human subjects

Radioactivity present in Route of Period (96 dose administered)

Subject adminis- Dose of study __ tration (PLg/k€!) (days) Urine Faeces Total

JB 1 JB I1 HP CGP

JB HP CGP

SM BO

p.0. p.0. p.0. p.0.

i.v. i.v. 1.v.

S.C.

S.C.

52 51 58 62

2.5 2.7 3.4

2.9 2.9

59.8 36.5 33.9 29.7

99.1 72.0 99.3

94.8 91.9

31.2 91 .O 58.4 94.9 62.0 95.9 58.9 88.6

2.7 101.8 2.3 74.3 2.8 102.1

2.5 97.3 2.7 94.6

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370 H. Torsten Nilsson, et al.

Figs. 4 and 5). It has also been shown that only a small amount (l'$i) of the dose is excreted in bile after intravenous administration, suggesting no impor- tance of enterohepatic circulation (Nilsson, H. T., Persson, C. G. & TegnCr, K., unpublished results). The excretion of the radioactivity after oral administra- tion is presented in Fig. 6 and Table 2. About one-third to one-half of the administered dose is recovered in the urine, and unchanged drug accounted for 6% of the dose, indicating that the drug is not readily absorbed. The remainder of the dose is recovered in the faeces.

I

I

2 4 6 8 1 0 1 2 Time af ter dosage (hour)

Fig. 4. Serum concentration of total radioactivity and unchanged terbutaline after intravenous administration of [ 3H]terbutaline to man. [ "ITerbutaline hydrobromide or sulphate (0.25 mg) was administered. Total radioactivity is expressed as terbutaline. Total radioactivity: 0 - - - 0 JB,

Unchanged terbutaline : 0- 0 JB, A-A - - - HP, 0 - - - 0 CGP. HP, m-m CGP.

The serum levels after intravenous and subcutaneous administration are shown in Figs. 4 and 5 and are almost uniform. A high proportion of free terbutaline is initially present and then the concentration of terbutaline decreases faster than that of total radioactivity. However, unchanged drug exceeds 50y0 of the total radioactivity up to two hours after administration. More than 9076 of the doses are recovered in urine after both routes and about 60% of the dose is excreted as unchanged drug (Figs. 7 and 8). Only a minor part (3%) is recovered in the faeces (Table 2).

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The Metabolism of Terbutaline in M a n

0) m 0

= 25- .u

0)

L V b) a

E

I .____ _ _ - - - - - - - + - - * J B I I , - - 1 -.--- --* - - - - - - - - - HP ’ _ - - - * - - -

) c _ - - -o- 1 5.- - ,**---

.-- ---*- - - - - - - - - o---* CGP

fi’ ,l 4 I ,,: *~ *- = - e J B I

- JB I1 - -

2 4 G 8 10 12 24 2 4 G 8 1 0 1’2 ’> 24

371

Time af ter dosage (hour) Serum concentration of total radioactivity and unchanged terbutaline after sub-

[3H]Terbutaline sulphate (0.25 mg) was administered. Total radioactivity is expressed as terbutaline. Total radioactivity: 0 - - - 0 SM, - - - BO. Unchanged terbutaline: 0- 0 SM, A-A BO.

Fig. 5. cutaneous administration [3H]terbutaline to man.

loo 1

m- - - -0- _ - - * -- - 4 J B I

,u ’

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372 H. Torsten Nilsson, et al.

100

75

W In 0 v

50 W m 0 + c b) U L 25 n

CGP

1

24 40 72 96

T ime a f t e r dosage ( h o u r )

intravenous administration of [ 3H]terbutaline to man. Fig. 7. Amounts of total radioactivity and unchanged terbutaline excreted in urine after

Total radio- Terbutaline hydrobromide or sulphate (0.25 mg) was administered. activity - - - , unchanged drug * - *.

loo,

W v) 0 V

W In 0 .u c W U L 0) n

BO , ’ .‘ - - - - SM

I

25- Q

I 24 48 72 96

Time a f t e r dosage ( h o u r )

subcutaneous administration of [3H]terbutaline to man. Fig. 8. Amounts of total radioactivity and unchanged terbutaline excreted in urine after

Total radioactivity - - - 0 , Terbutaline sulphate (0.25 mg) was administered. unchanged drug 0 - 0 .

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The Metabolism of Terbutaline in Man 373

Urine obtained after oral, intravenous and subcutaneous administration exhibits identical patterns when examined by electrophoresis and paper chroma- tography, indicating the same metabolic pathway in the biotransformation of terbutaline. Figure 2 (A) illustrates an electropherogram of untreated urine from the oral study. In all urine samples examined the metabolite is hydrolysed by a mixture of sulphatase and /3-glucuronidase (helicase (Fig. 2 (D)) which indicates that terbutaline is metabolized by conjugation. In the identification of the conjugate, further experiments with /3-glucuronidase (bovine or bacterial) and arylsulphatase (limpets) show that no appreciable hydrolysis occurred with /3-glucuronidase (Fig. 2 (B)). However, with arylsulphatase, peak I decreased and peak I1 increased correspondingly (Fig. 2 (C)) and after continuous incuba- tion for four days, the major part of the conjugate was hydrolysed. These results indicate that the metabolite is most likely a sulphate conjugate.

Thus after different routes of administration of the drug, no change in the metabolic fate is found, only the degree of conjugation varies. The low amount of unchanged drug excreted in urine after oral administration may reflect a biotransformation in the gut wall as proposed by Barr & Riegelmann (1970). After administration by any of the three routes, recoveries of radioactivity in 3-4 days are almost complete, the major part of the absorbed radioactivity being excreted via the urine in 24 h. From this data it is reasonable to conclude that terbutaline is not accumulated in the human body.

Acknowledgment We thank Miss Inger Svensson for excellent technical assistance, Sven

Carlstrom, M.D., Department of Medicine, University Hospital, Lund, for medical advice and Rertil Persson, Ph.D., Department of Radiophysics, Univer- sity Hospital, Lund, for calculations of the radiation doses.

References ARNER, B. (1970). Acta med. scand. suppl., 512, 45. BARR, W. H. & RIEGELMANN, S. (1970). BERGMAN, J., PERSSON, H. & WETTERLIN, K. (1969). BODIN, N. O., HANSSON, E., RAMSAY, C. H. & RYRFELDT, A. (1972).

DODGSON, K. S. & SPENCER, B. (1953). DORSCH, J. & ULMER, W. T. (1971). FORMGREN, H. (1970 a). FORMGREN, H. (1970 b). LEGGE, J. S., GADDIE, J. & PALMER, K. N. V. (1971). LEVINE, J. & DOYLE, T. D. (1967). J. Pharm. Sci. , 56, 619. MARTIN, L. E., HOBSON, J. C., PAGE, J. A. & HARRISON, C. (1971).

MODIN, R. & SCHILL, G. (1967). MORGAN, C. D., SANDLER, M., DAVIES, D. S., CONOLLY, M., PATERSON, J. W. & DOLLERY,

PERSSON, H. & OLSSON, T. (1970). PERSON, K. & PERSSON, K. (1972). RECOMMENDATIONS OF THE INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION,

TEMPLE, D. M. & GILLESPIE, R. (1966). WETTERLIN, K. I. L. & SVENSSON, L. A. (1968).

J. Pharm. Sci. , 59, 164. Experientia, 25, 899.

Actaphysiol. scand., 84, 40.

Biochem.J., 55, 315. Med. Kl in . , 66, 959.

Scand. J. resp. Dis. , 51, 195. Scand. J. resp. Dis., 51, 203.

B r . Med . J., 1, 637.

Eur. J. Pharmac., 14, 183.

Acta Pharm. Suecica, 4, 301.

C. T. (1969). Biochem. J., 114, 8P. Acta med. scand. suppl., 512, 11. Xenobiotica, 2, 375.

ICRP Publ. 10 (1968), Pergamon Press. Nature, Lond., 209, 714.

Belgium patent No. 704932.

2 c 2

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