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Chronopharmacological study of furosemide; (VII) influence of repeated administration on biochemical parameters in blood
Life Sciences, Vol. 47, pp. 2277-2281 Printed in the U.S.A.
Pergamon Press
CHRONOPHARMACOLOGICAL STUDY OF FUROSEMIDE; (V~) INFLUENCE OF REPEATED ADMINISTRATION ON BIOCHEMICAL PARAMETERS IN BLOOD Akio Fujimura, Kyo-ichi Ohashi and Akio Ebihara Department of Clinical Pharmacology, Jichi Medical School Minamikawachi-machi, Kawachi-gun, Tochigi 329-04, Japan (Received in final form October 9, 1990) Summary The present study was undertaken to examine whether influences of furosemide on biochemical parameters vary with its time of administration in Wistar rats. Rats were maintained under conditions of light (0700-1900 hrs) and dark (1900-0700 hrs). Furosemide (30 mg/kg) or vehicle (5% glucose) was given orally at I000 hrs (day trial) or at 2200 hrs (night trial) for 14 days. Water and food intakes were measured, and urine was collected for 24 hours following the final dosage in each group. Thereafter, blood samples were obtained. Water intake and urinary excretions of volume, sodium and chloride increased by furosemide treatment. The increments in these parameters were greater in the day trial than in the night trial. Food intake did not change. The serum concentration of chloride was decreased by furosemide. The decrement in this parameter was enhanced in the day trial. The influence of furosemide on other biochemical parameters (sodium, potassium, creatinine, calcium, inorganic phosphate, total protein, total cholesterol and glucose) did not differ between the day and night trials. These data indicate that the untoward influence of furosemide on serum chloride might vary with its time of administration.
Furosemide, a potent loop diuretic agent, is widely prescribed for the treatment of hypertension and congestive heart failure. However, untoward effects on biochemical parameters are observed in some patients during a longterm treatment with the agent (1). There is increasing evidence demonstrating time-dependent changes in effectiveness and toxicity of cardiovascular agents (2-6). Previous single and repeated administration studies have demonstrated that the diuretic effects of furosemide vary with its time of dosage (7-9). It is, therefore, anticipated that the influences of furosemide on biochemical parameters might also be affected by its administration time. To examine this hypothesis, furosemide was given orally to rats once a day in the morning or in the evening for 14 days. The influence of repeated administration of the agent on serum electrolytes, lipids and glucose were compared between morning and evening trials.
0024-3205/90 $3.00 + .00 Copyright (c) 1990 Pergamon Press plc
2278
Chronopharmacology of Furosemide
Vol. 47, No. 24, 1990
Materials and Methods Male Wistar rats (Charles River Laboratory, Kanagawa, Japan) at i0 weeks of age were maintained for more than 2 weeks under conditions of light from 0700 hrs to 1900 hrs and dark from 1900 hrs to 0700 hrs with free access to food and water. During the control period (day 0), 3 ml of 5% glucose solution (vehicle) was given into stomach at I000 hrs (day trial, n=16) or at 2200 hrs (night trial, n=16). Food and water intake were measured and urine was collected for 24 hours after administration of the vehicle. Thereafter, each group of rats was divided into two subgroups. One group (n=8) received 30 mg/kg of furosemide in 3 ml of vehicle at I000 hrs (or 2200 hrs) for 14 days. The other group (n=8) received 3 ml of vehicle alone at 1000 hrs (or 2200 hrs) for 14 days. The parameters obtained during the control period were also measured for 24 hours following the final dosage of furosemide or vehicle alone (day 14). Blood samples at 24 hours after the final administration were also obtained under pentobarbital anesthesia. Serum and urinary concentrations of electrolytes, and serum total protein and cholesterol were measured using an autoanalyzer (736, Hitachi, Tokyo, Japan). The serum glucose concentration was determined by a glucose oxidase method (Glucoroder, Shino Test, Tokyo, Japan). Urinary furosemide concentration was measured by Hoechst Japan Ltd. using high pressure liquid chromatography (I0). The results are expressed as means ± SEM. Data are analyzed by analysis of variance and Student's t test as appropriate.
Results During the control period, no significant difference was observed in any parameter between the vehicle and furosemide groups in the trials (FIG. i). The 24-hour water intake was slightly increased by the repeated dosage of furosemide at 2200 hr and significantly (p<0.05) increased following administration at i000 hr. There were no significant differences in food intake among these groups on day 14 (day trial; vehicle 18±3 g/day, furosemide ]6±3 g/day, night trial; vehicle 15±4 g/day, furosemide 18±4 g/day). The 24-hour excretions of volume, sodium and chloride was increased by the repeated administration of furosemide. The values of these parameters in the day trial were greater than those in the night trial (volume; 0.05
Vol. 47, No. 24, 1990
|
Chronopharmacology of Furosemide
-":] ,
o
,i!
r. iko.ol -i i
p,.~o.os ~ i
o
o~
day trial
night trial day 0
day trial
night trial
day 14
FIG. 1 Water intake and urinary excretion of volume, sodium, chloride and furosemide following repeated administration of furosemide at i000 hr (day trial) or at 2200 hr (night trial). The 24-hour water intake was determined and urine was collected during the control period (day O) and following the final dosage of furosemide (day 14). mean ± SEM = vehicle group, P ~ = furosemide group Vehicle (3 ml of 5% glucose) or furosemide (30 mg in 3 ml of vehicle) was given once a day at i000 hr (n~8 in each group) or at 2200 hr (n=8 in each group) for 14 days.
2279
2280
Chronopharmacology of Furosemide
Vol. 47, No. 24, 1990
TABLE i day trial
night trial
parameter vehicle (n=8) sodium, mEq/l
140±2
potassium,
I
mEq/l
4.6±0.1
chloride, mEq/l
furosemide (n=8) 139±I p
139±I
furosemide (n=8) 140±]
U--p
4.2±0.1
F---P
vehicle (n=8)
I
99±1
4.8±0.2 p
4.4±0.1 l 102±1
Serum concentrations of sodium, potassium and chloride following repeated administration of furosemide at I000 hr (day trial) or at 2200 hr (night trial). Vehicle (3 ml of 5% glucose) or furosemide (30 mg in 3 ml of vehicle) was given once a day at I000 hr or at 2200 hr for 14 days. Twenty-four hours after the final dosage, blood samples were obtained in each group, mean ± SEM
Discussion We have recently published data indicating that the urinary excretions of volume and sodium following a single administration of furosemide were greater when given at I000 hrs compared to those given at 2200 hrs in Wistar rats (7,8). The present study extends these observations to a repeated administration study over a period of 14 days. At the end of the treatment period, water intake following furosemide was greater in the day trial_than in the night trial. Since the sensation of thirst is stimulated by hypovolemia and elevated angiotensin ~ concentrations mediated through the diuretic action of furosemide (ll), the present study provides indirect evidence supporting a greater diuretic effect of the agent during daytime administration. Hypochloremia is sometimes observed during a prolonged treatment with furosemide (I). Chloride ion serves as a major regulatory mechanism of acidbase balance. Since hypochloremia is usually associated with metabolic alkalosis (i) which may cause tetany and electrocardiographic abnormality (12), it is important to prevent a deterioration in chloride homeostasis. The present animal study demonstrates that the decrease in serum chloride concentration is enhanced following the repeated dosage of furosemide at day-time. This finding indicates that the untoward influence of furosemide on serum chloride might vary with its administration time. The observation that the urinary excretion of chloride following furosemide was greater in the day trial than that in the night trial might, at least in part, explain this timedependent influence of the agent on serum chloride. In summary, the present study demonstrates that the decrease in serum chloride induced by the repeated dosage of furosemide at day-time is enhanced compared to that in the night trial. The influences of furosemide on other biochemical parameters did not differ between the day and night trials under
Vol. 47, No. 24, 1990
Chronopharmacology of Furosemide
2281
conditions of the present protocol. However, the possibility that the influence on other parameters might also vary with its time of administration can not be ruled out. Further studies with more prolonged treatment and more dosing points are needed to examine this hypothesis.
References I. F.G. McMAHON, Management of Essential Hypertension, Futura Publishing Company, INC., New York (1978). 2. B. LEMMER and A. CHARRIER, Naunyn-Schmiedeberg's Arch. Pharmacol. 313 205-212 (1980). 3. B. LEMMER, K. BATHE, A. CHARRIER, G. NEUMANN, D. SCHULZ and H. WINKLER, Toward Chronopharmacolosy, ed. by R. TAKAHASHI, F. HALBERG and C.A. WALKER, pp. 183-190, Pergamon Press, London (1982). 4. B. LEMMER, H. WINKLER, T. OHM and M. FINK, Naunyn-Schmiedeberg's Arch. Pharmacol. 330 42-49 (1985). 5. M. SMOLENSKY, J.A. JOVONOVICH, G.M. KYLE and B. HSI, Chronopharmacology, ed. by A. REINBERG and F. HALBERG, pp. 263-271, Pergamon Press, London (1979). 6. A. FUJIMURA, Y. KUMAGAI, H. KAJIYAMA and A. EBIHARA, Acta Pharmacol. et Toxicol. 59 432-433 (1986). 7. A. FUJIMURA and A. EBIHARA, Life Sci. 38 1215-1220 (1986). 8. A. FUJIMURA and A. EBIHARA, Life Sci. 42 1431-1437 • (1988). 9. F. DOR~, C. D'AUTEUIL, G. LABRECQUE and--P.M. BELANGER, Annual Review of Chronopharmacology, Vol. i, ed. by A. REINBERG, M. SMOLENSKY and G. LABRECQUE, pp. 313-316, Pergamon Press, London (1984). i0. M.L. MACDOUGALL, D.W. SHOEMAN and D.L. AZARNOFF, Research Communications in Chemical Pathology and Pharmacology 10285-291 (1975). ii. J.T. FITZSIMONS, The Physiology of Thirst and Sodium Appetite, Cambridge University Press, London (1979). 12. E. GOLDBERGER, A Primer of Water t Electrolyte and Acid-Base Syndromes, Lea & Febiger, Philadelphia (1980).
Pergamon Press
CHRONOPHARMACOLOGICAL STUDY OF FUROSEMIDE; (V~) INFLUENCE OF REPEATED ADMINISTRATION ON BIOCHEMICAL PARAMETERS IN BLOOD Akio Fujimura, Kyo-ichi Ohashi and Akio Ebihara Department of Clinical Pharmacology, Jichi Medical School Minamikawachi-machi, Kawachi-gun, Tochigi 329-04, Japan (Received in final form October 9, 1990) Summary The present study was undertaken to examine whether influences of furosemide on biochemical parameters vary with its time of administration in Wistar rats. Rats were maintained under conditions of light (0700-1900 hrs) and dark (1900-0700 hrs). Furosemide (30 mg/kg) or vehicle (5% glucose) was given orally at I000 hrs (day trial) or at 2200 hrs (night trial) for 14 days. Water and food intakes were measured, and urine was collected for 24 hours following the final dosage in each group. Thereafter, blood samples were obtained. Water intake and urinary excretions of volume, sodium and chloride increased by furosemide treatment. The increments in these parameters were greater in the day trial than in the night trial. Food intake did not change. The serum concentration of chloride was decreased by furosemide. The decrement in this parameter was enhanced in the day trial. The influence of furosemide on other biochemical parameters (sodium, potassium, creatinine, calcium, inorganic phosphate, total protein, total cholesterol and glucose) did not differ between the day and night trials. These data indicate that the untoward influence of furosemide on serum chloride might vary with its time of administration.
Furosemide, a potent loop diuretic agent, is widely prescribed for the treatment of hypertension and congestive heart failure. However, untoward effects on biochemical parameters are observed in some patients during a longterm treatment with the agent (1). There is increasing evidence demonstrating time-dependent changes in effectiveness and toxicity of cardiovascular agents (2-6). Previous single and repeated administration studies have demonstrated that the diuretic effects of furosemide vary with its time of dosage (7-9). It is, therefore, anticipated that the influences of furosemide on biochemical parameters might also be affected by its administration time. To examine this hypothesis, furosemide was given orally to rats once a day in the morning or in the evening for 14 days. The influence of repeated administration of the agent on serum electrolytes, lipids and glucose were compared between morning and evening trials.
0024-3205/90 $3.00 + .00 Copyright (c) 1990 Pergamon Press plc
2278
Chronopharmacology of Furosemide
Vol. 47, No. 24, 1990
Materials and Methods Male Wistar rats (Charles River Laboratory, Kanagawa, Japan) at i0 weeks of age were maintained for more than 2 weeks under conditions of light from 0700 hrs to 1900 hrs and dark from 1900 hrs to 0700 hrs with free access to food and water. During the control period (day 0), 3 ml of 5% glucose solution (vehicle) was given into stomach at I000 hrs (day trial, n=16) or at 2200 hrs (night trial, n=16). Food and water intake were measured and urine was collected for 24 hours after administration of the vehicle. Thereafter, each group of rats was divided into two subgroups. One group (n=8) received 30 mg/kg of furosemide in 3 ml of vehicle at I000 hrs (or 2200 hrs) for 14 days. The other group (n=8) received 3 ml of vehicle alone at 1000 hrs (or 2200 hrs) for 14 days. The parameters obtained during the control period were also measured for 24 hours following the final dosage of furosemide or vehicle alone (day 14). Blood samples at 24 hours after the final administration were also obtained under pentobarbital anesthesia. Serum and urinary concentrations of electrolytes, and serum total protein and cholesterol were measured using an autoanalyzer (736, Hitachi, Tokyo, Japan). The serum glucose concentration was determined by a glucose oxidase method (Glucoroder, Shino Test, Tokyo, Japan). Urinary furosemide concentration was measured by Hoechst Japan Ltd. using high pressure liquid chromatography (I0). The results are expressed as means ± SEM. Data are analyzed by analysis of variance and Student's t test as appropriate.
Results During the control period, no significant difference was observed in any parameter between the vehicle and furosemide groups in the trials (FIG. i). The 24-hour water intake was slightly increased by the repeated dosage of furosemide at 2200 hr and significantly (p<0.05) increased following administration at i000 hr. There were no significant differences in food intake among these groups on day 14 (day trial; vehicle 18±3 g/day, furosemide ]6±3 g/day, night trial; vehicle 15±4 g/day, furosemide 18±4 g/day). The 24-hour excretions of volume, sodium and chloride was increased by the repeated administration of furosemide. The values of these parameters in the day trial were greater than those in the night trial (volume; 0.05
Vol. 47, No. 24, 1990
|
Chronopharmacology of Furosemide
-":] ,
o
,i!
r. iko.ol -i i
p,.~o.os ~ i
o
o~
day trial
night trial day 0
day trial
night trial
day 14
FIG. 1 Water intake and urinary excretion of volume, sodium, chloride and furosemide following repeated administration of furosemide at i000 hr (day trial) or at 2200 hr (night trial). The 24-hour water intake was determined and urine was collected during the control period (day O) and following the final dosage of furosemide (day 14). mean ± SEM = vehicle group, P ~ = furosemide group Vehicle (3 ml of 5% glucose) or furosemide (30 mg in 3 ml of vehicle) was given once a day at i000 hr (n~8 in each group) or at 2200 hr (n=8 in each group) for 14 days.
2279
2280
Chronopharmacology of Furosemide
Vol. 47, No. 24, 1990
TABLE i day trial
night trial
parameter vehicle (n=8) sodium, mEq/l
140±2
potassium,
I
mEq/l
4.6±0.1
chloride, mEq/l
furosemide (n=8) 139±I p
139±I
furosemide (n=8) 140±]
U--p
4.2±0.1
F---P
vehicle (n=8)
I
99±1
4.8±0.2 p
4.4±0.1 l 102±1
Serum concentrations of sodium, potassium and chloride following repeated administration of furosemide at I000 hr (day trial) or at 2200 hr (night trial). Vehicle (3 ml of 5% glucose) or furosemide (30 mg in 3 ml of vehicle) was given once a day at I000 hr or at 2200 hr for 14 days. Twenty-four hours after the final dosage, blood samples were obtained in each group, mean ± SEM
Discussion We have recently published data indicating that the urinary excretions of volume and sodium following a single administration of furosemide were greater when given at I000 hrs compared to those given at 2200 hrs in Wistar rats (7,8). The present study extends these observations to a repeated administration study over a period of 14 days. At the end of the treatment period, water intake following furosemide was greater in the day trial_than in the night trial. Since the sensation of thirst is stimulated by hypovolemia and elevated angiotensin ~ concentrations mediated through the diuretic action of furosemide (ll), the present study provides indirect evidence supporting a greater diuretic effect of the agent during daytime administration. Hypochloremia is sometimes observed during a prolonged treatment with furosemide (I). Chloride ion serves as a major regulatory mechanism of acidbase balance. Since hypochloremia is usually associated with metabolic alkalosis (i) which may cause tetany and electrocardiographic abnormality (12), it is important to prevent a deterioration in chloride homeostasis. The present animal study demonstrates that the decrease in serum chloride concentration is enhanced following the repeated dosage of furosemide at day-time. This finding indicates that the untoward influence of furosemide on serum chloride might vary with its administration time. The observation that the urinary excretion of chloride following furosemide was greater in the day trial than that in the night trial might, at least in part, explain this timedependent influence of the agent on serum chloride. In summary, the present study demonstrates that the decrease in serum chloride induced by the repeated dosage of furosemide at day-time is enhanced compared to that in the night trial. The influences of furosemide on other biochemical parameters did not differ between the day and night trials under
Vol. 47, No. 24, 1990
Chronopharmacology of Furosemide
2281
conditions of the present protocol. However, the possibility that the influence on other parameters might also vary with its time of administration can not be ruled out. Further studies with more prolonged treatment and more dosing points are needed to examine this hypothesis.
References I. F.G. McMAHON, Management of Essential Hypertension, Futura Publishing Company, INC., New York (1978). 2. B. LEMMER and A. CHARRIER, Naunyn-Schmiedeberg's Arch. Pharmacol. 313 205-212 (1980). 3. B. LEMMER, K. BATHE, A. CHARRIER, G. NEUMANN, D. SCHULZ and H. WINKLER, Toward Chronopharmacolosy, ed. by R. TAKAHASHI, F. HALBERG and C.A. WALKER, pp. 183-190, Pergamon Press, London (1982). 4. B. LEMMER, H. WINKLER, T. OHM and M. FINK, Naunyn-Schmiedeberg's Arch. Pharmacol. 330 42-49 (1985). 5. M. SMOLENSKY, J.A. JOVONOVICH, G.M. KYLE and B. HSI, Chronopharmacology, ed. by A. REINBERG and F. HALBERG, pp. 263-271, Pergamon Press, London (1979). 6. A. FUJIMURA, Y. KUMAGAI, H. KAJIYAMA and A. EBIHARA, Acta Pharmacol. et Toxicol. 59 432-433 (1986). 7. A. FUJIMURA and A. EBIHARA, Life Sci. 38 1215-1220 (1986). 8. A. FUJIMURA and A. EBIHARA, Life Sci. 42 1431-1437 • (1988). 9. F. DOR~, C. D'AUTEUIL, G. LABRECQUE and--P.M. BELANGER, Annual Review of Chronopharmacology, Vol. i, ed. by A. REINBERG, M. SMOLENSKY and G. LABRECQUE, pp. 313-316, Pergamon Press, London (1984). i0. M.L. MACDOUGALL, D.W. SHOEMAN and D.L. AZARNOFF, Research Communications in Chemical Pathology and Pharmacology 10285-291 (1975). ii. J.T. FITZSIMONS, The Physiology of Thirst and Sodium Appetite, Cambridge University Press, London (1979). 12. E. GOLDBERGER, A Primer of Water t Electrolyte and Acid-Base Syndromes, Lea & Febiger, Philadelphia (1980).