European Journal of Clinical Pharmacology

Eur. J. Clin. Pharmacol. 16, 351-353 (1979)

© by Springer-Verlag 1979

Accelerated Fall in Serum Bromide Level After Administration of Perchlorate to Man S. Seyfert* PsychiatrischeKlinik der Freien UniversitfitBerlin, Germany

Summary. Five patients intoxicated with bromoureide showed accelerated elimination of bromide from serum after a single dose of perchlorate. It was probably due to increased renal excretion of bromide. Perchlorate has been reported to increase the renal clearance of other monovalent anions by inhibiting their tubular reabsorption and a similar interaction between perchlorate and bromide is suggested. Although perchlorate effectively eliminates bromide it should not replace chloride in the treatment of bromide intoxication, because of the side effects of its repeated administration. Key words: carbromal, bromoureide, bromide intoxication, perchlorate; sertun bromide elimination

A patient with chronic carbromal abuse, who was hospitalized for detoxication, showed a surprising increase in excretion of bromide in a follow-up mSnary bromide test. He was first suspected to have taken carbromal again, yet simultaneously the serum bromide had fallen more than expected. Known influences on bromide excretion, such as high chloride intake or forced diuresis, could be excluded. However, a brain scintigram had been performed with 99mpertechnetate and prior administration of sodium perchlorate. To answer the question whether these substances could have increased the bromide excretion by the patient, further patients with known bromoureide abuse were treated with perchlorate.

rate, as shown in the figure. The serum bromide concentration was determined by means of an ion-sensitive electrode [8, 9]. Diuretics or halogen-containing drugs were omitted during the observation period. q~e patients were kept on the usual hospital food. No patient had unusual eating or drinking habits. The figure shows the regression lines (and biological elimination half-lives) calculated in each patient from the bromide values before and after perchlorate. The slopes of the two regression lines were almost equal in each patient, but the post-perchlorate regression lines were all shifted downwards. This indicates that perchlorate had briefly accelerated bromide elimination. The change was estimated from the difference between the first post-perchlorate serum bromide value and the corresponding virtual bromide value extrapolated from the pre-perchlorate regression line. The change was in the range of 0.2-0.79 mmol bromide/1 serum, and it seemed to be proportional to the serum half-life of bromide. In two patients (W. G., ID-No. 113043592, and K.S., IDNo. 217114332), serum bromide was followed from the day of hospitalization.Surprisingly,the bromide levelrose during the first few days, even though further drug intake was unlikely. These bromide values were excludedfrom the calculations.Both patients had taken carbromal chronically and probably had developed a gastro-intestinal deposit of carbromal [4, 16]. One of them had in addition ingested a large dose of carbromal shortly before admission to hospital. Deposited carbromal may raise the serum bromide level for severaldays even after drug intake has ceased [3, 4, 13, 151.

Discussion Methods and Results Four further inpatients were tested after giving their informed consent. Blood samples were taken before and after a single dose of 1200 mg sodium perchlo* Present address: NeurologischeKlinik der Freien Universit~it, Klinikum Steglitz,Berlin, Germany

All five patients showed accelerated elimination of serum bromide after perchlorate. The corresponding urinary bromide excretion was increased in the one patient in whom it was determined (T. H., IDNo. 106073887). This suggests that perchlorate increases the renal clearance of bromide. Perchlorate has been reported to increase the renal clearance of two other halogen ions, chloride [5] and iodide [5,

352

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Fig. 1 Decrease in serum bromide level before andafter perchlorate administration in 5 patients intoxicated with bromoureide. z~ signifies accelerated decrease following perchlorate. Patient T. H. (ID-No. 106073887), ~ , 38 yrs. 40 tab. Betadorm~/week (Carbroma1480 mg/tab.), tv2 before perchlorate 15.9 days, t,/2after perchlorate 16.5 days, ~ = 0,79 mmol bromide/1 serum. Patient G.G. (ID-No. 120011222), Cf, 66yrs. 8-10 tab. Halbmond®/day (Carbromal 350mg, Bromisoval 150 mg/tab.). %2 before perchlorate 10.2 days, t~/2after perchlorate 11.8 days, A = 0.53 mmol bromide/l serum. Patient W. G. (ID-No. 113043592), C¢, 43 yrs. At least 2 tab. Hoggar®/day, 40 tab. Hoggar ® over 3 days before hospital admission (Carbromal 500 rag/tab.), t,/2 before perchtorate 10.3 days, t w after perchlorate 8.1 days, 2x = 0.35 mmol bromide/1 serttm. Patient K.S. (ID-No. 217114332), ~, 35 yrs. 8 tab. Betadorm®/day (Carbromal 480 rag/tab.), tv~ before perchlorate 7.3 days, t,/2 after perchlorate 9.8 days, z5 = 0.35 mmoI bromide/1 serum. Patient L. K. (ID-No. 103093748), C~, 41 yrs. 10-15 tab. Adalin®/day (Carbromal 500 mg/tab.), t,/~before perchlorate 6.1 days, t,/2 after perchlorate 8.8 days, A = 0.2 mmol bromide/l serum.

S. Seyfert: Perchtorate and Bromide Elimination 12]; it is b e l i e v e d b y inhibiting their t u b u l a r r e a b sorption. P e r h a p s p e r c h l o r a t e also inhibits the t u b u lar r e a b s o r p t i o n of b r o m i d e and in that w a y increases its renal clearance. A n u m b e r of similar interactions h a v e b e e n d e m o n s t r a t e d : chloride increases the renal clearance of b r o m i d e [10, 18] and of iodide [5], b r o m i d e increases that of iodide [5], iodide a n d t h i o c y a n a t e increase t h a t of p e r c h l o r a t e [19], a n d p e r c h l o r a t e increases that of t h i o c y a n a t e [2, 17]. It m a y well be that all these m o n o v a l e n t anions increase e a c h others renal clearance. T h e cause is t h o u g h t to b e c o m p e t i tion for t u b u l a r r e a b s o r p t i o n , at least b e t w e e n the halogen anions [5, 10, 11, 17, 18]. In o u r five patients the m o l a r quantities of t h e a d m i n i s t e r e d p e r c h l o r a t e and of the e l i m i n a t e d b r o m i d e were in a similar range. P e r c h l o r a t e is not m e t a b o l i z e d in m a n [1]. T h e possibility that the m o n o v a l e n t anion p e r t e c h n e t a t e c o n t r i b u t e d to the fall in s e r u m b r o m i d e in the first patient (T. H.) can be rejected, since the dose of 10 mCi99mpertechnetate is e q u i v a l e n t to the negligibly small a m o u n t of 2 × 10 -8 retool. T h e m o n o v a l e n t anions m e n t i o n e d also interact in o t h e r organs [2, 6, 7, 12, 14, 19, 20]. This u n d e r lines their biological similarity a n d suggests a n o t h e r m e a n s by which p e r c h l o r a t e might increase the renal e x c r e t i o n of b r o m i d e . P e r c h l o r a t e inhibits the u p t a k e a n d c o n c e n t r a t i o n of m o n o v a l e n t anions into several organs, e. g. that of iodide into the thyroid gland [19, 20], the salivary glands [14] a n d the gastric m u c o s a [12], a n d of t h i o c y a n a t e into the b r e a s t [2] a n d salivary glands [14]. P e r c h l o r a t e also displaces m o n o v a l e n t anions f r o m these o r g a n s into the serum, e. g., iodide f r o m the thyroid gland [19, 20], a n d possibly f r o m the salivary glands [14]. In this w a y p e r c h l o r a t e increases the c o n c e n t r a t i o n of these anions in s e r u m a n d s u b s e q u e n t l y in the r e n a l tubule. This increased quantity of anions m a y in turn inhibit the t u b u l a r r e a b s o r p t i o n of m o n o v a l e n t anions, e . g . , b r o m i d e , and so e n h a n c e their excretion. A c k n o w l e d g e m e n t . T h e m e t h o d for d e t e r m i n i n g s e r u m b r o m i d e w a s d e v e l o p e d by Prof. D r . B. Miill e r - O e r l i n g h a u s e n , w h o m I wish to t h a n k also for his critical a n d helpful discussion of the p a p e r .

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353 4. Grosse, G., H6fer, W., Gruska, H., Beyer, K.-H., Kubicki, S., Schirop, T.: Zur Klinik der schweren Carbromal-Intoxikation. Klin. Wochenschr. 52, 39-49 (1974) 5. Halmi, N. S., King, L. T., Widner, R. R., Hass, A. C., Stuelke, R. G.: Renal excretion of radioiodide in rats. Am. J. Physiol. 193, 379-385 (1958) 6. Harden, R. McG., Alexander, W.D., Shimmins, J., Russel, R.I.: Quantitative uptake measurements of 99m Tc in salivary glands and stomach and concentration of 99m Tc, t32j and 82Br in gastric juice and saliva. In: Radioaktive Isotope in Klinik und Forschung. Fellinger, K., H6fer, R. (eds.), Vol. VIII, pp. 77-87. Miinchen: Urban & Schwarzenberg 1968 7. Harden, R. McG., Alexander, W. D., Shimmins, J., Chisholm, D.: A comparison between the gastric and salivary concentration of iodide, pertechnetate, and bromide in man. Gut 10, 928-930 (1969) 8. MOller-Oerlinghausen, B., KlingenfuB, B., Poser, S., Poser, W.: Bedeutung und klinisch-chemische Diagnostik des chronischen Abusus bromhaltiger Schlafmittel. Med. Klin. 70, 1784-1789 (1975) 9. Poser, S., Poser, W., Miiller-Oerlinghausen, B.: Use of bromide electrodes for rapid screening of etevated bromide concentration in biological fluids. Z. Chem. Klin. Biochem. 12, 350-351 (1974) 10. Rauws, A.G., van Logten, M.J.: The influence of dietary" chloride on bromide excretion in the rat. Toxicology 3, 29-32 (1975) 11. Schafer, J.A., Vander, A.J., Brubacher, E.E.: Anion concentration gradients and electrical potentials in distal tubule of dog. Am. J. Physiol. 210, 1285-1289 (1966) 12. Seh6nbaum, E., Sellers, E. A., Gill, M. J.: Some effects of perchlorate on the distribution of 131-iodine. Acta Endocrinol. 50, 195-201 (1965) 13. Sch/itz, H., Ha, I.D.: Bromidkonzentrationen im Ham nach der Einnahme therapeutischer und suizidaler Dosen Carbromal. Arzneim. Forsch. 25, 432-435 (1975) 14. Stephen, K.W., Robertson, J.W.K., Harden, R.McG., Chisholm, D.M.: Concentration of iodide, per~echnetate, thiocyanate, and bromide in saliva from parotid, submandibular, and minor salivary glands in man. J. Lab. Clin. Med. 81, 219-229 (1973) 15. Vohland, H.-W., Hadisoemarto, S., Wanke, B.: Zur Toxikotogie von Carbromal. I. Erfassung yon Carbromal und wirksamen Metaboliten bei Ratte und Mensch. Arch. Toxicol. 36, 31-42 (1976) 16. Vohland, H.-W., Hadisoemarto, S., Wanke, B.: Zur Toxikologie yon Carbromal. II. Pharmakokinetik yon Carbromal und einigen wirksamen Metaboliten in der Ratte. Arch. Toxicol. 37, 275-288 (1977) 17. Walser, M., Rahill, W.J.: Nitrate, thiocyanate, and perchlorate clearance in relation to chloride clearance. Am. J. Physiol. 208, 1158-1164 (1965) 18. Wolf, R.L., Eadie, G.S.: Reabsorption of bromide by the kidney. Am. J. Physiol. 163, 436-441 (1950) 19. Wolff, J.: Transport of iodide and other anions in the thyroid gland. Physiol. Rev. 44, 45-90 (1964) 20. Wyngaarden, J. B., Wright, B. M., Ways, P.: The effect of certain anions upon the accumulation and retention of iodide by the thyroid gland. Endocrinology 50, 537-549 (1952) Received: January 18, 1979, accepted in revised form: June 30, 1979 Dr. S. Seyfert Neurologische Universit~itsklinik Klinikum Steglitz Hindenburgdamm 30 D-1000 Berlin 45, Germany