Archives of
Deermatological
Arch. Dermatoi. Res. 266, 103-108 (1979)
searcn
9 Springer-Verlag 1979
Original Works The Effect of Antifungal Agents on Pancreatic and Gastric Secretion in Rats Yoon-Kee Park 1, Sungnack Lee 1, Won Joon Kim 2, and Sa Suk Hong 2 1 Department of Dermatology z Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
Summary. This study was designed to investigate the effects of griseofulvin, 5fluorocytosine (5-FC), and amphotericin B on pancreatic and gastric secretion after the administration of a single large dose, or repeated small doses for 3 weeks, in male albino rats. The exocrine fuctions of the main digestive glands were only slightly affected by griseofulvin and were not affected by 5-FC. In contrast, a single large dose of amphotericin B caused a marked inhibition of exocrine functions of the main digestive glands. The rats treated with 5-FC lost body weight markedly during 2 weeks of administration. Key words: Griseofulvin - 5-fluorocytosine (5-FC) - Amphotericin B Pancreaticobiliary secretion - Gastric secretion
Zusammenfassung. Diese Studie diente der Uberprtifung des Einflusses von Griseofulvin, 5-fluorocytosine (5-FC) und Amphotericin B auf die Pankreasund Magensekretion nach Verabreichung einer einmaligen hohen Dosis oder wiederholten kleineren Dosen ftir 3 Wochen bei 224 m/innlichen AlbinoRatten. Die exocrinen Funktionen der Hauptverdauungsdriisen waren von Griseofulvin nut leicht und von 5-FC gar nicht beeintr/ichtigt. Im Gegensatz dazu verursachte eine einmalige hohe Dosis von Amphotericin B eine deutliche Inhibition der exocrinen Funktion der Hauptverdauungsdriisen. Die Ratten, die mit 5-FC behandelt wurden, verminderten deutlich ihr Gewicht nach wiederholter Verabreichung in 2 Wochen. Schliisselwiirter: Griseofulvin - 5-fluorocytosine (5-FC) - Amphotericin B Pancreaticobili/ire Sekretion - Magensekretion It is clinically known that griseofulvin, 5-fluorocytosine (5-FC), and amphotericin B are used effectively in the treatment of superficial dermatophytosis and deep fungal diseases. However, the problems of treatment with these drugs Offprint requests to. Yoon-Kee Park, M.D. (address see above)
0340-3696/79/0266/0103/$1.20
104
Y.-K. Park et al.
have been associated with their toxicity. Digestive disturbances a n d skin rashes occurred occasionally d u r i n g 5 - F C treatment. Leukopenia, t h r o m b o c y t o p e n i a , a n d a b n o r m a l i t i e s of liver f u n c t i o n occurred b u t rarely [12]. The toxicity of a m p h o t e r i c i n B was more a p p a r e n t a n d includes even anaphylaxis [1]. I n fact, the study of these side effects of therapy have become a n i m p o r t a n t p a r t of research projects. Moreover, it is n o t k n o w n w h a t effect these a n t i f u n g a l agents have o n the exocrine functions of the m a i n digestive glands. O u r study was u n d e r t a k e n to investigate the effect of griseofulvin, 5-FC, a n d a m p h o t e r i c i n B on pancreatic a n d gastric secretion in rats d u r i n g b o t h short- a n d long-term administration.
Materials and Methods Two hundred twenty-four hybrid male albino rats weighing 180 g were employed for this study. Griseofulvin, 5-FC, and amphotericin B were used. For the experiment of pancreatico-biliary secretion, griseofulvin2.5 g/kg or 5-FC 1 g/kg was given orally in a distilled water suspension 1 h before the study. Amphotericin B, 5 mg/kg, or 15 mg/kg, was administered intraperitoneally (i.p.) to another group using a single injection. For the experiment of gastric secretion, the agents were given intraduodenally just before pyloric ligation. In the groups given long-term administration, griseofulvin as a suspension of 2 % arabia gum, 50 mg/kg, or 1 g/kg, in distilled water was given orally. 5-FC or amphotericin B was given i.p. 100 mg/kg, or 1 mg/kg, daily for 3 weeks.
Measurement of Pancreatico-Biliary Enzymes All animals were not fed for 24 h and only given water before the experiment. The abdominal wall was incisedunder secobarbital anesthesia (30 mg/kg), and the common bile duct was cannulated with a fine polyethylenetube (0.98 mm o.d.). The mixedbile and pancreaticjuice was collectedfor 2 h. Amylasewas determinedby the method of Sumner [13]. Lipase was determined by the method of Cherry and Crandall [3]. The levels of cholate and bilirubin were determined by the methods of Irvin et al. [5] and Magee et al. [7], respectively.
Measurement of Gastric Secretion and Acidity All rats were left without any food and housed individually in cages with raised bottoms of wide wire mesh to avoid coprophage for 48 h. Under light ether anesthesia a pyloric ligature was placed by the procedure describedby Shay et al. [10]. The animals were killed 5 h after pyloric ligation, and the gastric juice was collected. The volume was measured (ml/h/100 g body wt.) and pH of the juice was determined by Titrator TTT2b(Radiometer, Copenhagen). Free and total acid was determined by Titrator TTTzb connected to Autoburette ABO 11 (Radiometer).
Results
Body Weight Changes I n rats the rate of growth after a d m i n i s t r a t i o n of griseofulvin or a m p h o t e r i c i n B was n o r m a l . However, the growth rate of rats treated with 5 - F C was m a r k e d l y retarded (Table 1).
Pancreatico-Biliary Secretion a) Single large dose a d m i n i s t r a t i o n groups. G r i s e o f u l v i n caused a n increase only in cholate a n d i n d u c e d n o changes in the other enzymes. 5-FC also caused n o changes
Antifungal Agents on Pancreatic and Gastric Secretion
105
Table 1. Effect of anti-mycotic agents on body weight in rats after repeated administration for 2 weeks Group
No. of rats
Body weight (g) Before
Control Griseofulvin Fluorocytosine Amphotericin B
35 20 25 24
175.4 175.9 180.4 176.4
_+ 3.19 +_ 4.69 _+ 2.68 _+ 4.05
After 1 week
After 2 weeks
190.1 189.7 183.9 187.0
200.8 199.7 183.8 194.2
+_ 3.19 +_ 4.55 +_ 2.78* + 3.83
+_ 3.50 _+ 4.47 _+ 2.99** +_ 4.24
* P< 0.01 ** P < 0.001
Table 2, Effect of anti-mycotic agents on pancreaticobiliary secretion in rats after single administration of massive doses Group
No. Volume of (ml/h/ rats 100gb. wt.)
Control 18 Griseofutvin" 8 Fluorocytosine b 9 Amphotericin B c 9 Amphotericin B d 13
0.37+-0.045 0.36 -+0.026 0.34-+0.028 0.34+-0.028 0.30+0.020
Bilirubin (mg/h/ 100gb. wt.)
Cholate Lipase (rag/h/ (ml N/ 1 0 0 g b . wt.) 20NaOH/h 100 g b. wt.)
2.1+_0.17 2.0 +-0.17 2.1+0.22 1.4+_0.07" 1.4+-0.08"
1.9_+0.22 2.8+_0.21" 1.6-+0.17 1.3_+ 0.11 1.5_+0.34
Amylase (rag maltose/h/ 1 0 0 g b . wt.)
49.1+ 7.27 1850_+305.8 50.2+_ 7.92 1939+_230.8 44.1_+10.53 1484+_288.8 29.3_+ 3.37 740+141.2' 20.8+_ 3.81" 559_+115.9'*
a b c d
Griseofulvin: 2.5 g/kg in water suspension, oral route Fluorocytosine: 1.0 g/kg in water, oral route Amphotericin B : 5 mg/kg i.p. Amphotericin B: 15 mg/kg i.p. * P < 0.05 ** P < 0.01
Table 3. Effect of anti-mycotic agents on pancreaticobiliary secretion in rats after repeated administration for 3 weeks Group
No. Volume Bilirubin Cholate Lipase of (ml/h/ (mg/h/ (rag/h/ (ml N/ rats 1 0 0 g b . wt.) 1 0 0 g b . wt.) 1 0 0 g b . wt.) 2 0 N a O H / h 100 g b. wt.)
Amylase (rag maltose/h/ t 0 0 g b , wt.)
Control Griseofulvin a Griseofulvin b Fluorocytosine ~ Amphotericin B d
15 12 9 12 11
2472_+703.2 2438_+423.3 2612+_520.4 2378+_287.8 3335+_41.4.4
b c a *
0.39_+0.038 0.43+_0.047 0.33_+0.039 0.35+_0.029 0.49+_0.050
2.1 _+0.19 2.0_+0.20 1.7_+0.20 2.2_+0.20 2.1+_0.26
50 mg/kg in arabia gum suspension, oral route 1000 mg/kg in water suspension, oral route Fluorocytosine: 100 mg/kg i.p. Amphotericin B : I mg/kg i.p. P < 0.05
1.1 +_0.18 1.4+_0.27 1.3+-0.10 1.3_+0.10 1.1+_0.19
49.0+_ 8.19 62.0_+ 8.89 87.3+_12.40" 40.3+_ 4.21 82.6_+10.09
106
Y.-K. Park et al.
Table 4. Effect of anti-mycotic agents on gastric secretion in rats after single administration of massive doses Group
No. of Volume rats (ml/h/ 100 g b. wt.)
pH
Free acid (uEg/h/ 100 g b. wt.)
Total acid (uEg/h/ 100 g b. wt.)
Control Griseofulvina Fluorocytosineb Amphotericin B~ Amphotericin Bd
16 10 10 9 12
1.28+_0.010 1.39+_0.081 1.45+_0.046 1.87• 2.94•
39.2+_3.67 52.2+-4.95* 35.9+_9.35 ll.4+-4.74"* 3.7•
59.5+_ 4.75 92.4+- 4.28* 53.3+-11.78 24.8+- 5.41"* 15.8_+ 4.21"**
0.68+-0.037 0.99+-0.048* 0.66+-0.117 0.35+-0.051"* 0.28+_0.038***
a Griseofulvin: 2.5 g/kg in water suspension, oral route b Fluorocytosine: 1 g/kg in water suspension, oral route Amphotericin B : 5 mg/kg i.p. a Amphotericin B: 15 mg/kg i.p. * P < 0.05 ** P < 0.01 **~ P < 0.001
Table 5, Effect of anti-mycotic agents on gastric secretion in rats after repeated administration for 3 weeks Group
No. of rats
Volume pH (ml/h/ 100 g b. wt.)
Free acid Total acid (uEg/h/ (uEg/h/ 100 g b. wt.) 100 g b. wt.)
Control Griseofulvin" Griseofulvinb Fluorocytosinec Amphotericin Bd
15 9 6 11 10
0.56_+0.112 1.49_+0.047 0.64• 1.39• 0.58+_0.104 1.58+_0.097 0.61 _+0.050 1.50+_0.049 0.63+-0.025 1.38_+0.017
29.1+_3.48 34.5+_5.37 19.9+_6.78" 36.7+-5.57 32.2+_3.16
44.6• 5.99 55.0• 37.4+ 9.75 51.9+_ 6.04 50.8+- 4.21
a 50 mg/kg in arabia gum suspension, oral route b 1,000 mg/kg in water suspension, oral route Fluorocytosine : 100 mg/kg i.p. a Amphotericin B: 1 mg/kg i.p. * P < 0.05
in the enzymes. A m p h o t e r i c i n B (5 mg/kg) caused a decrease in b i l i r u b i n a n d amylase secretion b u t caused n o changes in cholate a n d lipase. F u r t h e r m o r e , a n increased dose of a m p h o t e r i c i n B (15 mg/kg) caused a decrease in bilirubin, lipase, and a significant decrease in amylase secretion (Table 2). b) L o n g - t e r m a d m i n i s t r a t i o n groups. Griseofulvin e n h a n c e d only lipase secretion. 5 - F C a n d a m p h o t e r i c i n B caused n o significant changes in pancreaticobiliary secretion (Table 3).
Gastric Secretion a) Single large dose a d m i n i s t r a t i o n groups. Griseofulvin caused a n increase in the v o l u m e of gastric secretion a n d in the o u t p u t of free acid a n d total acid. 5 - F C caused n o significant changes in gastric juice. A m p h o t e r i c i n B caused a significant
Antifungal Agents on Pancreatic and Gastric Secretion
107
decrease in the volume, in free acid, and total acid of the gastric juice, while the pH was increased remarkably. Furthermore, like the pancreatico-bilary secretion in the animals given increased doses of amphotericin B, the gastric secretion was greatly inhibited (Table 4). b) Long-term administration groups. Griseofulvin, 5-FC, and amphotericin B caused no significant changes in the volume of gastric secretion or acid output (Table 5). Discussion
Bilirubin, lipase, and amylase secretion were diminished after a single large administration of amphotericin B. Furthermore, amylase secretion was more markedly inhibited when the dose was increased. However, long-term treatment with amphotericin B caused no significant changes in panereatico-biliary secretion. The significant decrease of amylase secretion is similar to the in vitro study of Singh et al. [11], in which it is reported that amphotericin B impairs pancreatic amylase secretion without altering tissue amylase content and transport of amylase from ribosomes to zymogen gr/mules. Amphotericin B has been shown to damage human red blood cells [2]. Moreover, the drug produces renal vasoconstriction and reduces renal blood flow, and has a direct toxic action on renal tubules [1]. Therefore, we believe a single large dose also affects the exocrine functions of the main digestive glands. Griseofulvin enhanced cholate and lipase secretion; however, the volume of pancreatico-biliary secretion, bilirubin or amylase, showed no significant changes. Sharpe and Tomich [9] reported that histological studies, after the rats had been maintained on the diet containing griseofulvin for 12 or 151/2 months, respectively, revealed no abnormalities. All liver function tests showed no abnormalities following prolonged administration of griseofulvin [6]. In our study, therefore, it is consistent that the pancreatico-biliary function showed no abnormalities. 5-FC caused no significant changes in pancreatico-biliary function whether given by single or a repeated dose regimen. Abnormalities of liver function, seen in less than 10 ~ of patients treated with 5-FC, were probably dose related and cleared after completion of therapy [12]. Elevations of serum glutamic oxalacetic transaminase and alkaline phosphatase have been seen occasionally but histologic evidence of hepatotoxicity was lacking [14, 15]. These reports, therefore, lend support to our results. In gastric secretion, griseofulvin caused an elevation in the volume and the acid output of gastric juice. This finding is in agreement with the suggestions of Goldman [4] and Prazak et al. [8], that griseofulvin given orally in humans may cause nausea and vomiting. Amphotericin B caused an inhibition in the volume and acid output of gastric juice and was dose related. These results were also in accord with the experiment of pancreatico-biliary secretion. 5-FC caused no significant changes in gastric secretion when administered either in small or large doses; however, the growth rate of rats treated with 5-FC was markedly retarded. This seems to be caused by indigestion and loss of appetite after 5-FC intake.
]08
Y.-K. Park et al.
From these data it may be concluded that the exocrine functions of the main digestive glands are only slightly affected by griseofulvin and are not affected by 5FC. However, excessive administration of amphotericin B has a significant effect on the exocrine functions of the main digestive glands in the rat. Acknowledgement. We are grateful to Dr. Y.S.Ahn and Dr. M.S. Lee of the Department of Pharmacology, Yonsei University, for their expert assistance in this work. We wish to thank Dr. R. Lasserre of Roche Far East Research Foundation for generous supplies of 5-FC.
References 1. Butler, W. T. : Pharmacology, toxicity and therapeutic usefulness of amphotericin B. J. Am. Med. Ass. 195, 371-375 (1966) 2. Butler, W. T., Alling, D. W., Cotlove, E. : Potassium loss fi'om human erythrocytes exposed to amphotericin B. Proc. Soc. Exp. Biol. Med. 118, 297--300 (1965) 3. Cherry, I. S., Crandall, L. A. Jr. : The specificity of pancreatic injury. Am. J. Physiol. 100, 266 - 273 (1932) 4. Goldman, L.: Griseofulvin. Med. Clin. North Am. 54, 1339-1345 (1970) 5. Irvin, J. L., Johnson, C. G., Kopala, J. : A photometric method for the determinations of cholates in blood and bile. J. Biochem. 153, 439-457 (1944) 6. Livingood, C. S., Brannen, M., Orders, R. L., Kopstein, J. B., Rebuck, J. W. : Effect of prolonged griseofulvin administration on liver, hematopoietic system, and kidney. Arch. Dermatol. 81, 760 765 (1960) 7. Magee, D. F., Kim, K. S., Ivy, A. C. : Action of some systemic choleretic compounds in chronic biliary fistula dogs. Am. J. Physiol. 169, 317-325 (1952) 8. Prazak, G., Ferguson, J. S., Comer, J. E., McNeil, B.S. : Treatment of tinea pedis with griseofulvin. Arch. Dermatol. 81, 821 826 (1960) 9. Sharpe, H. M., Tomich, E. G. : Studies in the toxicology of griseofulvin. Toxicol. Appl. Pharmacol. 2, 4 4 - 5 3 (1960) 10. Shay, H., Komarov, S. A., Fels, S. S., Meranz, D., Gluenstein, M., Siplet, H. : A simple method for the uniform production of gastric ulceration in the rat. Gastroenterology 5, 4 3 - 61 (1945) 11. Singh, M., Black, O., Webster, P. D. : Effect of drugs on pancreatic amylase secretion in vitro. Gastroenterology 63, 4 4 9 - 457 (1972) 12. Steer, P. L., Marks, M. I., Klite, P. D., Eickhaff, T. C.: 5-Fluorocytosine: An oral antifungal compound. Ann. Int. Med. 76, 1 5 - 2 2 (1972) 13. Sumner, J. B. : The estimation of sugar in diabetic urine using dinitrosalicylate. J. Biol. Chem. 62, 287 (1924) 14. Utz, J. P. : New drugs for the systemic mycoses: Flucytosine and clotrimazole. Bull. NY. Acad. Med. 51, 1103-1108 (1975) 15. Vandevelde, A. G., Mauceri, A. A., Johnson III, J. E. : 5-fluorocytosine in the treatment of mycotic infections. Ann. Int. Med. 77, 4 3 - 5 1 (1972) Received February 12, 1979
Deermatological
Arch. Dermatoi. Res. 266, 103-108 (1979)
searcn
9 Springer-Verlag 1979
Original Works The Effect of Antifungal Agents on Pancreatic and Gastric Secretion in Rats Yoon-Kee Park 1, Sungnack Lee 1, Won Joon Kim 2, and Sa Suk Hong 2 1 Department of Dermatology z Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
Summary. This study was designed to investigate the effects of griseofulvin, 5fluorocytosine (5-FC), and amphotericin B on pancreatic and gastric secretion after the administration of a single large dose, or repeated small doses for 3 weeks, in male albino rats. The exocrine fuctions of the main digestive glands were only slightly affected by griseofulvin and were not affected by 5-FC. In contrast, a single large dose of amphotericin B caused a marked inhibition of exocrine functions of the main digestive glands. The rats treated with 5-FC lost body weight markedly during 2 weeks of administration. Key words: Griseofulvin - 5-fluorocytosine (5-FC) - Amphotericin B Pancreaticobiliary secretion - Gastric secretion
Zusammenfassung. Diese Studie diente der Uberprtifung des Einflusses von Griseofulvin, 5-fluorocytosine (5-FC) und Amphotericin B auf die Pankreasund Magensekretion nach Verabreichung einer einmaligen hohen Dosis oder wiederholten kleineren Dosen ftir 3 Wochen bei 224 m/innlichen AlbinoRatten. Die exocrinen Funktionen der Hauptverdauungsdriisen waren von Griseofulvin nut leicht und von 5-FC gar nicht beeintr/ichtigt. Im Gegensatz dazu verursachte eine einmalige hohe Dosis von Amphotericin B eine deutliche Inhibition der exocrinen Funktion der Hauptverdauungsdriisen. Die Ratten, die mit 5-FC behandelt wurden, verminderten deutlich ihr Gewicht nach wiederholter Verabreichung in 2 Wochen. Schliisselwiirter: Griseofulvin - 5-fluorocytosine (5-FC) - Amphotericin B Pancreaticobili/ire Sekretion - Magensekretion It is clinically known that griseofulvin, 5-fluorocytosine (5-FC), and amphotericin B are used effectively in the treatment of superficial dermatophytosis and deep fungal diseases. However, the problems of treatment with these drugs Offprint requests to. Yoon-Kee Park, M.D. (address see above)
0340-3696/79/0266/0103/$1.20
104
Y.-K. Park et al.
have been associated with their toxicity. Digestive disturbances a n d skin rashes occurred occasionally d u r i n g 5 - F C treatment. Leukopenia, t h r o m b o c y t o p e n i a , a n d a b n o r m a l i t i e s of liver f u n c t i o n occurred b u t rarely [12]. The toxicity of a m p h o t e r i c i n B was more a p p a r e n t a n d includes even anaphylaxis [1]. I n fact, the study of these side effects of therapy have become a n i m p o r t a n t p a r t of research projects. Moreover, it is n o t k n o w n w h a t effect these a n t i f u n g a l agents have o n the exocrine functions of the m a i n digestive glands. O u r study was u n d e r t a k e n to investigate the effect of griseofulvin, 5-FC, a n d a m p h o t e r i c i n B on pancreatic a n d gastric secretion in rats d u r i n g b o t h short- a n d long-term administration.
Materials and Methods Two hundred twenty-four hybrid male albino rats weighing 180 g were employed for this study. Griseofulvin, 5-FC, and amphotericin B were used. For the experiment of pancreatico-biliary secretion, griseofulvin2.5 g/kg or 5-FC 1 g/kg was given orally in a distilled water suspension 1 h before the study. Amphotericin B, 5 mg/kg, or 15 mg/kg, was administered intraperitoneally (i.p.) to another group using a single injection. For the experiment of gastric secretion, the agents were given intraduodenally just before pyloric ligation. In the groups given long-term administration, griseofulvin as a suspension of 2 % arabia gum, 50 mg/kg, or 1 g/kg, in distilled water was given orally. 5-FC or amphotericin B was given i.p. 100 mg/kg, or 1 mg/kg, daily for 3 weeks.
Measurement of Pancreatico-Biliary Enzymes All animals were not fed for 24 h and only given water before the experiment. The abdominal wall was incisedunder secobarbital anesthesia (30 mg/kg), and the common bile duct was cannulated with a fine polyethylenetube (0.98 mm o.d.). The mixedbile and pancreaticjuice was collectedfor 2 h. Amylasewas determinedby the method of Sumner [13]. Lipase was determined by the method of Cherry and Crandall [3]. The levels of cholate and bilirubin were determined by the methods of Irvin et al. [5] and Magee et al. [7], respectively.
Measurement of Gastric Secretion and Acidity All rats were left without any food and housed individually in cages with raised bottoms of wide wire mesh to avoid coprophage for 48 h. Under light ether anesthesia a pyloric ligature was placed by the procedure describedby Shay et al. [10]. The animals were killed 5 h after pyloric ligation, and the gastric juice was collected. The volume was measured (ml/h/100 g body wt.) and pH of the juice was determined by Titrator TTT2b(Radiometer, Copenhagen). Free and total acid was determined by Titrator TTTzb connected to Autoburette ABO 11 (Radiometer).
Results
Body Weight Changes I n rats the rate of growth after a d m i n i s t r a t i o n of griseofulvin or a m p h o t e r i c i n B was n o r m a l . However, the growth rate of rats treated with 5 - F C was m a r k e d l y retarded (Table 1).
Pancreatico-Biliary Secretion a) Single large dose a d m i n i s t r a t i o n groups. G r i s e o f u l v i n caused a n increase only in cholate a n d i n d u c e d n o changes in the other enzymes. 5-FC also caused n o changes
Antifungal Agents on Pancreatic and Gastric Secretion
105
Table 1. Effect of anti-mycotic agents on body weight in rats after repeated administration for 2 weeks Group
No. of rats
Body weight (g) Before
Control Griseofulvin Fluorocytosine Amphotericin B
35 20 25 24
175.4 175.9 180.4 176.4
_+ 3.19 +_ 4.69 _+ 2.68 _+ 4.05
After 1 week
After 2 weeks
190.1 189.7 183.9 187.0
200.8 199.7 183.8 194.2
+_ 3.19 +_ 4.55 +_ 2.78* + 3.83
+_ 3.50 _+ 4.47 _+ 2.99** +_ 4.24
* P< 0.01 ** P < 0.001
Table 2, Effect of anti-mycotic agents on pancreaticobiliary secretion in rats after single administration of massive doses Group
No. Volume of (ml/h/ rats 100gb. wt.)
Control 18 Griseofutvin" 8 Fluorocytosine b 9 Amphotericin B c 9 Amphotericin B d 13
0.37+-0.045 0.36 -+0.026 0.34-+0.028 0.34+-0.028 0.30+0.020
Bilirubin (mg/h/ 100gb. wt.)
Cholate Lipase (rag/h/ (ml N/ 1 0 0 g b . wt.) 20NaOH/h 100 g b. wt.)
2.1+_0.17 2.0 +-0.17 2.1+0.22 1.4+_0.07" 1.4+-0.08"
1.9_+0.22 2.8+_0.21" 1.6-+0.17 1.3_+ 0.11 1.5_+0.34
Amylase (rag maltose/h/ 1 0 0 g b . wt.)
49.1+ 7.27 1850_+305.8 50.2+_ 7.92 1939+_230.8 44.1_+10.53 1484+_288.8 29.3_+ 3.37 740+141.2' 20.8+_ 3.81" 559_+115.9'*
a b c d
Griseofulvin: 2.5 g/kg in water suspension, oral route Fluorocytosine: 1.0 g/kg in water, oral route Amphotericin B : 5 mg/kg i.p. Amphotericin B: 15 mg/kg i.p. * P < 0.05 ** P < 0.01
Table 3. Effect of anti-mycotic agents on pancreaticobiliary secretion in rats after repeated administration for 3 weeks Group
No. Volume Bilirubin Cholate Lipase of (ml/h/ (mg/h/ (rag/h/ (ml N/ rats 1 0 0 g b . wt.) 1 0 0 g b . wt.) 1 0 0 g b . wt.) 2 0 N a O H / h 100 g b. wt.)
Amylase (rag maltose/h/ t 0 0 g b , wt.)
Control Griseofulvin a Griseofulvin b Fluorocytosine ~ Amphotericin B d
15 12 9 12 11
2472_+703.2 2438_+423.3 2612+_520.4 2378+_287.8 3335+_41.4.4
b c a *
0.39_+0.038 0.43+_0.047 0.33_+0.039 0.35+_0.029 0.49+_0.050
2.1 _+0.19 2.0_+0.20 1.7_+0.20 2.2_+0.20 2.1+_0.26
50 mg/kg in arabia gum suspension, oral route 1000 mg/kg in water suspension, oral route Fluorocytosine: 100 mg/kg i.p. Amphotericin B : I mg/kg i.p. P < 0.05
1.1 +_0.18 1.4+_0.27 1.3+-0.10 1.3_+0.10 1.1+_0.19
49.0+_ 8.19 62.0_+ 8.89 87.3+_12.40" 40.3+_ 4.21 82.6_+10.09
106
Y.-K. Park et al.
Table 4. Effect of anti-mycotic agents on gastric secretion in rats after single administration of massive doses Group
No. of Volume rats (ml/h/ 100 g b. wt.)
pH
Free acid (uEg/h/ 100 g b. wt.)
Total acid (uEg/h/ 100 g b. wt.)
Control Griseofulvina Fluorocytosineb Amphotericin B~ Amphotericin Bd
16 10 10 9 12
1.28+_0.010 1.39+_0.081 1.45+_0.046 1.87• 2.94•
39.2+_3.67 52.2+-4.95* 35.9+_9.35 ll.4+-4.74"* 3.7•
59.5+_ 4.75 92.4+- 4.28* 53.3+-11.78 24.8+- 5.41"* 15.8_+ 4.21"**
0.68+-0.037 0.99+-0.048* 0.66+-0.117 0.35+-0.051"* 0.28+_0.038***
a Griseofulvin: 2.5 g/kg in water suspension, oral route b Fluorocytosine: 1 g/kg in water suspension, oral route Amphotericin B : 5 mg/kg i.p. a Amphotericin B: 15 mg/kg i.p. * P < 0.05 ** P < 0.01 **~ P < 0.001
Table 5, Effect of anti-mycotic agents on gastric secretion in rats after repeated administration for 3 weeks Group
No. of rats
Volume pH (ml/h/ 100 g b. wt.)
Free acid Total acid (uEg/h/ (uEg/h/ 100 g b. wt.) 100 g b. wt.)
Control Griseofulvin" Griseofulvinb Fluorocytosinec Amphotericin Bd
15 9 6 11 10
0.56_+0.112 1.49_+0.047 0.64• 1.39• 0.58+_0.104 1.58+_0.097 0.61 _+0.050 1.50+_0.049 0.63+-0.025 1.38_+0.017
29.1+_3.48 34.5+_5.37 19.9+_6.78" 36.7+-5.57 32.2+_3.16
44.6• 5.99 55.0• 37.4+ 9.75 51.9+_ 6.04 50.8+- 4.21
a 50 mg/kg in arabia gum suspension, oral route b 1,000 mg/kg in water suspension, oral route Fluorocytosine : 100 mg/kg i.p. a Amphotericin B: 1 mg/kg i.p. * P < 0.05
in the enzymes. A m p h o t e r i c i n B (5 mg/kg) caused a decrease in b i l i r u b i n a n d amylase secretion b u t caused n o changes in cholate a n d lipase. F u r t h e r m o r e , a n increased dose of a m p h o t e r i c i n B (15 mg/kg) caused a decrease in bilirubin, lipase, and a significant decrease in amylase secretion (Table 2). b) L o n g - t e r m a d m i n i s t r a t i o n groups. Griseofulvin e n h a n c e d only lipase secretion. 5 - F C a n d a m p h o t e r i c i n B caused n o significant changes in pancreaticobiliary secretion (Table 3).
Gastric Secretion a) Single large dose a d m i n i s t r a t i o n groups. Griseofulvin caused a n increase in the v o l u m e of gastric secretion a n d in the o u t p u t of free acid a n d total acid. 5 - F C caused n o significant changes in gastric juice. A m p h o t e r i c i n B caused a significant
Antifungal Agents on Pancreatic and Gastric Secretion
107
decrease in the volume, in free acid, and total acid of the gastric juice, while the pH was increased remarkably. Furthermore, like the pancreatico-bilary secretion in the animals given increased doses of amphotericin B, the gastric secretion was greatly inhibited (Table 4). b) Long-term administration groups. Griseofulvin, 5-FC, and amphotericin B caused no significant changes in the volume of gastric secretion or acid output (Table 5). Discussion
Bilirubin, lipase, and amylase secretion were diminished after a single large administration of amphotericin B. Furthermore, amylase secretion was more markedly inhibited when the dose was increased. However, long-term treatment with amphotericin B caused no significant changes in panereatico-biliary secretion. The significant decrease of amylase secretion is similar to the in vitro study of Singh et al. [11], in which it is reported that amphotericin B impairs pancreatic amylase secretion without altering tissue amylase content and transport of amylase from ribosomes to zymogen gr/mules. Amphotericin B has been shown to damage human red blood cells [2]. Moreover, the drug produces renal vasoconstriction and reduces renal blood flow, and has a direct toxic action on renal tubules [1]. Therefore, we believe a single large dose also affects the exocrine functions of the main digestive glands. Griseofulvin enhanced cholate and lipase secretion; however, the volume of pancreatico-biliary secretion, bilirubin or amylase, showed no significant changes. Sharpe and Tomich [9] reported that histological studies, after the rats had been maintained on the diet containing griseofulvin for 12 or 151/2 months, respectively, revealed no abnormalities. All liver function tests showed no abnormalities following prolonged administration of griseofulvin [6]. In our study, therefore, it is consistent that the pancreatico-biliary function showed no abnormalities. 5-FC caused no significant changes in pancreatico-biliary function whether given by single or a repeated dose regimen. Abnormalities of liver function, seen in less than 10 ~ of patients treated with 5-FC, were probably dose related and cleared after completion of therapy [12]. Elevations of serum glutamic oxalacetic transaminase and alkaline phosphatase have been seen occasionally but histologic evidence of hepatotoxicity was lacking [14, 15]. These reports, therefore, lend support to our results. In gastric secretion, griseofulvin caused an elevation in the volume and the acid output of gastric juice. This finding is in agreement with the suggestions of Goldman [4] and Prazak et al. [8], that griseofulvin given orally in humans may cause nausea and vomiting. Amphotericin B caused an inhibition in the volume and acid output of gastric juice and was dose related. These results were also in accord with the experiment of pancreatico-biliary secretion. 5-FC caused no significant changes in gastric secretion when administered either in small or large doses; however, the growth rate of rats treated with 5-FC was markedly retarded. This seems to be caused by indigestion and loss of appetite after 5-FC intake.
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Y.-K. Park et al.
From these data it may be concluded that the exocrine functions of the main digestive glands are only slightly affected by griseofulvin and are not affected by 5FC. However, excessive administration of amphotericin B has a significant effect on the exocrine functions of the main digestive glands in the rat. Acknowledgement. We are grateful to Dr. Y.S.Ahn and Dr. M.S. Lee of the Department of Pharmacology, Yonsei University, for their expert assistance in this work. We wish to thank Dr. R. Lasserre of Roche Far East Research Foundation for generous supplies of 5-FC.
References 1. Butler, W. T. : Pharmacology, toxicity and therapeutic usefulness of amphotericin B. J. Am. Med. Ass. 195, 371-375 (1966) 2. Butler, W. T., Alling, D. W., Cotlove, E. : Potassium loss fi'om human erythrocytes exposed to amphotericin B. Proc. Soc. Exp. Biol. Med. 118, 297--300 (1965) 3. Cherry, I. S., Crandall, L. A. Jr. : The specificity of pancreatic injury. Am. J. Physiol. 100, 266 - 273 (1932) 4. Goldman, L.: Griseofulvin. Med. Clin. North Am. 54, 1339-1345 (1970) 5. Irvin, J. L., Johnson, C. G., Kopala, J. : A photometric method for the determinations of cholates in blood and bile. J. Biochem. 153, 439-457 (1944) 6. Livingood, C. S., Brannen, M., Orders, R. L., Kopstein, J. B., Rebuck, J. W. : Effect of prolonged griseofulvin administration on liver, hematopoietic system, and kidney. Arch. Dermatol. 81, 760 765 (1960) 7. Magee, D. F., Kim, K. S., Ivy, A. C. : Action of some systemic choleretic compounds in chronic biliary fistula dogs. Am. J. Physiol. 169, 317-325 (1952) 8. Prazak, G., Ferguson, J. S., Comer, J. E., McNeil, B.S. : Treatment of tinea pedis with griseofulvin. Arch. Dermatol. 81, 821 826 (1960) 9. Sharpe, H. M., Tomich, E. G. : Studies in the toxicology of griseofulvin. Toxicol. Appl. Pharmacol. 2, 4 4 - 5 3 (1960) 10. Shay, H., Komarov, S. A., Fels, S. S., Meranz, D., Gluenstein, M., Siplet, H. : A simple method for the uniform production of gastric ulceration in the rat. Gastroenterology 5, 4 3 - 61 (1945) 11. Singh, M., Black, O., Webster, P. D. : Effect of drugs on pancreatic amylase secretion in vitro. Gastroenterology 63, 4 4 9 - 457 (1972) 12. Steer, P. L., Marks, M. I., Klite, P. D., Eickhaff, T. C.: 5-Fluorocytosine: An oral antifungal compound. Ann. Int. Med. 76, 1 5 - 2 2 (1972) 13. Sumner, J. B. : The estimation of sugar in diabetic urine using dinitrosalicylate. J. Biol. Chem. 62, 287 (1924) 14. Utz, J. P. : New drugs for the systemic mycoses: Flucytosine and clotrimazole. Bull. NY. Acad. Med. 51, 1103-1108 (1975) 15. Vandevelde, A. G., Mauceri, A. A., Johnson III, J. E. : 5-fluorocytosine in the treatment of mycotic infections. Ann. Int. Med. 77, 4 3 - 5 1 (1972) Received February 12, 1979
