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Influence of erythromycin and terbinafine on liquid gastric emptying in healthy volunteers
CURRENT THERAPEUTIC RESEARCH VOL. 54, NO. 2, AUGUST1993
INFLUENCE OF ERYTHROMYCIN AND TERBINAFINE ON LIQUID GASTRIC EMPTYING IN HEALTHY VOLUNTEERS MARIETA VAN WYK, DE KLERK SOMMERS, JACQUES R. SNYMAN, AND JOAN MONCRIEFF Department of Pharmacology, University of Pretoria, Pretoria, South Africa
ABSTRACT This s t u d y was c o n d u c t e d to investigate t h e effects o f e r y t h r o m y c i n and t e r b i n a f i n e on g a s t r i c e m p t y i n g of liquids in h e a l t h y volunteers, by e v a l u a t i n g t h e p r o p o r t i o n a l c u m u l a t i v e a r e a u n d e r t h e curve (PCAuc) of p a r a c e t a m o l as an index o f g a s t r i c emptying. A l t h o u g h n o t significant, t h e r e was a t r e n d for e r y t h r o m y c i n to a c c e l e r a t e g a s t r i c e m p t y i n g . F r o m 15 m i n u t e s onward, t e r b i n a f i n e reduced the PCAuc of p a r a c e t a m o l s i g n i f i c a n t l y , i n d i c a t i n g a d e l a y in gastric e m p t y i n g . E r y t h r o m y c i n , a k n o w n a g o n i s t at m o t i l i n receptors, g e n e r a l l y influences g a s t r i c e m p t y i n g in a dose-dependent m a n n e r ; however, doses used in this study m i g h t have been insufficient to produce a s i g n i f i c a n t a c c e l e r a t i n g effect on g a s t r i c e m p t y i n g . This study c o n f i r m s results o b t a i n e d w i t h t e r b i n a f i n e in rodents. A l t h o u g h t h e m e c h a n i s m is still u n c l e a r , this delay is h y p o t h e s i z e d as e i t h e r a n a n t i m o t i l i n effect o r due to m o d u l a t i o n o f 5 - h y d r o x y t r y p t a m i n e - s t i m u l a t e d a c e t y l c h o l i n e release.
INTRODUCTION
Terbinafine, an allylamine derivative of naftifine, is an example of a new chemical class of antimycotics with great antifungal potential. It is active after both topical and oral administration. Terbinafine interferes with squalene epoxidase and affects the synthesis of ergosterol and cholesterol. 1 Fortunately, squalene epoxidase in fungi is 30,000 times more sensitive to the pharmacologic action of terbinafine than it is in humans.1 Terbinafine is generally well tolerated, but approximately 5% of patients experience mild transient gastrointestinal symptoms (eg, a feeling of fullness, dyspepsia, and nausea). 2 These appear to be due to an effect of terbinafine in delaying gastric emptying. 3 Erythromycin, a 14-member macrolide compound, mimics the effect of the gastrointestinal polypeptide motilin on gastrointestinal motility, probably by acting as an agonist at its recepAddress correspondenceto: Dr. Marieta Van Wyk, Department of Pharmacology, University of Pretoria, P.O. Box 2034, 0001 Pretoria, South Africa. Received for publication on April 19, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 186
0011-393X/93/$3.50
M. VAN WYK ET AL.
tors, 4 thus causing commonly reported gastrointestinal side effects, namely nausea, vomiting, cramping, upper abdominal pain, and diarrhea. 5 The purpose of this study was to measure liquid gastric emptying devised~ (ie, the proportional cumulative area under the curve [PCAu C] of paracetamol) to evaluate the influence of terbinafine and erythromycin on gastric emptying in healthy volunteers. M A T E R I A L S AND M E T H O D S
Six healthy male volunteers, mean age 23 years (range, 21 to 29 years) and mean weight 71.3 kg (range, 63 to 80 kg), participated in the study. They were requested to abstain from strenuous exercise, alcohol, and caffeinecontaining beverages for at least 24 hours before test startup. Written informed consent was obtained from all volunteers after the protocol had been approved by the Ethics Committee of the University of Pretoria. On each occasion, at time 0, 1.5 gm of paracetamol* (three 500-mg tablets) plus 250 ml of water was administered to each volunteer. Blood samples were taken at 5, 10, 15, 30, 45, 60, 120, and 480 minutes after paracetamol administration for analyzing and calculating paracetamol blood levels. A crossover randomized sequence design was followed, allowing at least a 2-week interval between the various regimens. This protocol was followed without pretreatment, or with pretreatment of either 250 mg of erythromycint base (one 250-mg capsule containing enteric-coated pellets) administered orally at -13, - 9 , and - 1 . 5 hours, or 250 mg of terbinafine$ (one 250-mg tablet; half-life = 16 hr) given on four evenings preceding study startup, before bedtime. Gastric emptying after the various regimens was calculated from paracetamol data, using the PCAu c method, ie, the amount of paracetamol absorbed at various time intervals after pretreatment; (AUC t) expressed as a proportion of the total amount of paracetamol given alone, absorbed over 2 hours (AUCo~2): AUCt PCAuc
--
AUCo~2 "
At each time interval, pairwise comparisons of interest between regimens were performed using Wilcoxon's matched-pair, signed-ranks test at the 0.05 level of significance.
* Trademark: Panado ® (Saphar-Med, Johannesburg, South Africa). t Trademark: Erymax ® (Parke-Davis, Cape Town, South Africa). Trademark: Lamisil ® (Sandoz Products, Johannesburg, South Africa).
187
EFFECTS OF ERYTHROMYCINfrERBINAFINEON GASTRIC EMPTYING
RESULTS AND DISCUSSION
Although not significant, there was a trend for erythromycin to accelerate liquid gastric emptying. From 15 minutes onwards, terbinafine significantly reduced the PCAu C of paracetamol, indicating a delay in liquid gastric emptying (table, figure). Since erythromycin's potential for accelerating liquid gastric emptying appears much greater than those of metoclopramide and cisapride, 7 it is noteworthy that in our study erythromycin only showed a trend in that direction. The prokinetic effect of erythromycin may be more pronounced when gastric smooth muscle function is impaired and when gastroparesis occurs as part of generalized autonomic neuropathy, as in diabetes. 4 The absence of side effects and the finding that erythromycin showed only a slight tendency to accelerate gastric emptying can partly be explained by the smaller dose (approximately 3.5 mg/kg) used in the present study; in other studies, a 7-mg/kg dose was used. s The delaying effect of terbinafine on gastric emptying in rodents was not ascribed to local irritation or histopathologic changes, but to a functional effect. In humans, transient gastrointestinal symptoms usually appeared in the first week of drug use; however, use of the higher dose, 500 mg, produces a more frequent occurrence of symptoms.2 It is likely that delayed gastric emptying might cause distress in patients with hiatus hernia, gastric or duodenal ulcer disease, or special awareness of gastric fullness. Such patients may not be able to tolerate terbinafine. 3 Although the mechanism of terbinafine-induced delay in gastric emptying is still unclear, it is unlikely to be due to anticholinergic effects, since no such side effects were experienced in the present study. Dyspeptic symptoms similar to those occurring with terbinafine are often reported with octreotide, a long-acting inhibitor of growth hormone release. The latter agent also causes hypomotility of the gut, which is hypothesized as either an antimotilin effect9 or due to modulation of 5-hydroxytryptamineTable. P e r c e n t of proportional c u m u l a t i v e a r e a u n d e r t h e c u r v e (PCAuc) of p a r a c e t a m o l a t e a c h t i m e i n t e r v a l a f t e r t h e v a r i o u s r e g i m e n s (n = 6). ( V a l u e s a r e e x p r e s s e d as m e a n -+ SEM.) Time (min) Regimens
5
10
15
Paracetamol alone Paracetamol plus terbinafine Paracetamol plus erythromycin
1.0 -+ 0.6
4.2 -+ 2.7
7.6 _+ 4.5
0 + 0
0.2 _+ 0.2
0.8 -+ 0.3*
0 -+ 0
3.5 -+ 1.2
8.6 -+ 2.7
30 17.8 _+ 7.1 4.3 -+ 0.8* 27.7 -+ 6.5
* P < 0.05, compared with paracetamol alone.
188
45
60
120
31.0 -+ 7.4
45.8 -+ 6.2
100 +_ 0
11.8 -+ 2.3*
23.0 -+ 3,7"
72.8 -+ 8.1"
44.5 -+ 7.6
59.3 -+ 8.4
111.7 -+ 10.7
M. VAN WYK ET AL.
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Time (min) Figure. M e a n values (n = 6) of t h e p e r c e n t of proportional c u m u l a t i v e area u n d e r t h e curve as a n index of gastric emptying. [ ] - - - [:3, P a r a c e t a m o l alone; * - - - * , p a r a c e t a m o l plus terbinafine; -~ -- - ÷ , paracetamol plus erythromycin.
stimulated acetylcholine release. 1° It is possible that similar explanations may be applied to terbinafine-induced gastric hypomotility.
Acknowledgment This study was supported in part by a research grant from the Medical 189
EFFECTSOFERYTHROMYCIN/TERBINAFINEONGASTRICEMPTYING
Research Council and the Department of Pharmacology, University of Pretoria, Pretoria, South Africa. References: 1. Ryder NS. The mechanism of action of terbinafine. ClinExpDermatol 1989; 14:98-100. 2. Villars V, Jones TC. Clinical efficacy and tolerability of terbinafine (Lamisil)--A new topical and systemic fungicidal drug for treatment of dermatomycoses. Clin Exp Dermatol 1989; 14:124-127. 3. Villars V, Jones TC. Present status of the efficacy and tolerability of terbinafine (Lamisil) used systemically in the treatment of dermatomycoses of the skin and nails. J Dermatol Treat 1990; l(Suppl 2):33-38. 4. Janssens J, Peeters TL, Vantrappen G, Tack J, et al. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. New Engl J Med 1990; 322:1028-1031. 5. Catnach SM, Fairclough PD. Review: Erythromycin and the gut. Gut 1992; 33:397-401. 6. Van Wyk M, Sommers De K, Snyman JR, Moncrieff J. A foreshortened method of measuring liquid gastric emptying in normal volunteers. Methods Find Exp Clin Pharmacol 1993; 15:61-66. 7. Vantrappen G. Erythromycin--The prokinetic drug of the future. Have we heard this story line before? Gastroenterology 1990; 99:559-568. 8. Zara GP, Qin XY, Pilot MA, et al. Erythromycin and gastrointestinal motility. Lancet 1987; 2:1036. 9. Depoortere I, Peeters TL, Vantrappen G. Erythromycin modulates motilin receptor density in rabbit. Gastroenterology 1989; 96:Al19. 10. Yau WM, Dorsett JA, Youther ML. Modulation of submucosal cholinergic neurons by 5-hydroxytryptamine and neuropeptides. Am J Physiol 1990; 259:G1019-G1024.
190
INFLUENCE OF ERYTHROMYCIN AND TERBINAFINE ON LIQUID GASTRIC EMPTYING IN HEALTHY VOLUNTEERS MARIETA VAN WYK, DE KLERK SOMMERS, JACQUES R. SNYMAN, AND JOAN MONCRIEFF Department of Pharmacology, University of Pretoria, Pretoria, South Africa
ABSTRACT This s t u d y was c o n d u c t e d to investigate t h e effects o f e r y t h r o m y c i n and t e r b i n a f i n e on g a s t r i c e m p t y i n g of liquids in h e a l t h y volunteers, by e v a l u a t i n g t h e p r o p o r t i o n a l c u m u l a t i v e a r e a u n d e r t h e curve (PCAuc) of p a r a c e t a m o l as an index o f g a s t r i c emptying. A l t h o u g h n o t significant, t h e r e was a t r e n d for e r y t h r o m y c i n to a c c e l e r a t e g a s t r i c e m p t y i n g . F r o m 15 m i n u t e s onward, t e r b i n a f i n e reduced the PCAuc of p a r a c e t a m o l s i g n i f i c a n t l y , i n d i c a t i n g a d e l a y in gastric e m p t y i n g . E r y t h r o m y c i n , a k n o w n a g o n i s t at m o t i l i n receptors, g e n e r a l l y influences g a s t r i c e m p t y i n g in a dose-dependent m a n n e r ; however, doses used in this study m i g h t have been insufficient to produce a s i g n i f i c a n t a c c e l e r a t i n g effect on g a s t r i c e m p t y i n g . This study c o n f i r m s results o b t a i n e d w i t h t e r b i n a f i n e in rodents. A l t h o u g h t h e m e c h a n i s m is still u n c l e a r , this delay is h y p o t h e s i z e d as e i t h e r a n a n t i m o t i l i n effect o r due to m o d u l a t i o n o f 5 - h y d r o x y t r y p t a m i n e - s t i m u l a t e d a c e t y l c h o l i n e release.
INTRODUCTION
Terbinafine, an allylamine derivative of naftifine, is an example of a new chemical class of antimycotics with great antifungal potential. It is active after both topical and oral administration. Terbinafine interferes with squalene epoxidase and affects the synthesis of ergosterol and cholesterol. 1 Fortunately, squalene epoxidase in fungi is 30,000 times more sensitive to the pharmacologic action of terbinafine than it is in humans.1 Terbinafine is generally well tolerated, but approximately 5% of patients experience mild transient gastrointestinal symptoms (eg, a feeling of fullness, dyspepsia, and nausea). 2 These appear to be due to an effect of terbinafine in delaying gastric emptying. 3 Erythromycin, a 14-member macrolide compound, mimics the effect of the gastrointestinal polypeptide motilin on gastrointestinal motility, probably by acting as an agonist at its recepAddress correspondenceto: Dr. Marieta Van Wyk, Department of Pharmacology, University of Pretoria, P.O. Box 2034, 0001 Pretoria, South Africa. Received for publication on April 19, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 186
0011-393X/93/$3.50
M. VAN WYK ET AL.
tors, 4 thus causing commonly reported gastrointestinal side effects, namely nausea, vomiting, cramping, upper abdominal pain, and diarrhea. 5 The purpose of this study was to measure liquid gastric emptying devised~ (ie, the proportional cumulative area under the curve [PCAu C] of paracetamol) to evaluate the influence of terbinafine and erythromycin on gastric emptying in healthy volunteers. M A T E R I A L S AND M E T H O D S
Six healthy male volunteers, mean age 23 years (range, 21 to 29 years) and mean weight 71.3 kg (range, 63 to 80 kg), participated in the study. They were requested to abstain from strenuous exercise, alcohol, and caffeinecontaining beverages for at least 24 hours before test startup. Written informed consent was obtained from all volunteers after the protocol had been approved by the Ethics Committee of the University of Pretoria. On each occasion, at time 0, 1.5 gm of paracetamol* (three 500-mg tablets) plus 250 ml of water was administered to each volunteer. Blood samples were taken at 5, 10, 15, 30, 45, 60, 120, and 480 minutes after paracetamol administration for analyzing and calculating paracetamol blood levels. A crossover randomized sequence design was followed, allowing at least a 2-week interval between the various regimens. This protocol was followed without pretreatment, or with pretreatment of either 250 mg of erythromycint base (one 250-mg capsule containing enteric-coated pellets) administered orally at -13, - 9 , and - 1 . 5 hours, or 250 mg of terbinafine$ (one 250-mg tablet; half-life = 16 hr) given on four evenings preceding study startup, before bedtime. Gastric emptying after the various regimens was calculated from paracetamol data, using the PCAu c method, ie, the amount of paracetamol absorbed at various time intervals after pretreatment; (AUC t) expressed as a proportion of the total amount of paracetamol given alone, absorbed over 2 hours (AUCo~2): AUCt PCAuc
--
AUCo~2 "
At each time interval, pairwise comparisons of interest between regimens were performed using Wilcoxon's matched-pair, signed-ranks test at the 0.05 level of significance.
* Trademark: Panado ® (Saphar-Med, Johannesburg, South Africa). t Trademark: Erymax ® (Parke-Davis, Cape Town, South Africa). Trademark: Lamisil ® (Sandoz Products, Johannesburg, South Africa).
187
EFFECTS OF ERYTHROMYCINfrERBINAFINEON GASTRIC EMPTYING
RESULTS AND DISCUSSION
Although not significant, there was a trend for erythromycin to accelerate liquid gastric emptying. From 15 minutes onwards, terbinafine significantly reduced the PCAu C of paracetamol, indicating a delay in liquid gastric emptying (table, figure). Since erythromycin's potential for accelerating liquid gastric emptying appears much greater than those of metoclopramide and cisapride, 7 it is noteworthy that in our study erythromycin only showed a trend in that direction. The prokinetic effect of erythromycin may be more pronounced when gastric smooth muscle function is impaired and when gastroparesis occurs as part of generalized autonomic neuropathy, as in diabetes. 4 The absence of side effects and the finding that erythromycin showed only a slight tendency to accelerate gastric emptying can partly be explained by the smaller dose (approximately 3.5 mg/kg) used in the present study; in other studies, a 7-mg/kg dose was used. s The delaying effect of terbinafine on gastric emptying in rodents was not ascribed to local irritation or histopathologic changes, but to a functional effect. In humans, transient gastrointestinal symptoms usually appeared in the first week of drug use; however, use of the higher dose, 500 mg, produces a more frequent occurrence of symptoms.2 It is likely that delayed gastric emptying might cause distress in patients with hiatus hernia, gastric or duodenal ulcer disease, or special awareness of gastric fullness. Such patients may not be able to tolerate terbinafine. 3 Although the mechanism of terbinafine-induced delay in gastric emptying is still unclear, it is unlikely to be due to anticholinergic effects, since no such side effects were experienced in the present study. Dyspeptic symptoms similar to those occurring with terbinafine are often reported with octreotide, a long-acting inhibitor of growth hormone release. The latter agent also causes hypomotility of the gut, which is hypothesized as either an antimotilin effect9 or due to modulation of 5-hydroxytryptamineTable. P e r c e n t of proportional c u m u l a t i v e a r e a u n d e r t h e c u r v e (PCAuc) of p a r a c e t a m o l a t e a c h t i m e i n t e r v a l a f t e r t h e v a r i o u s r e g i m e n s (n = 6). ( V a l u e s a r e e x p r e s s e d as m e a n -+ SEM.) Time (min) Regimens
5
10
15
Paracetamol alone Paracetamol plus terbinafine Paracetamol plus erythromycin
1.0 -+ 0.6
4.2 -+ 2.7
7.6 _+ 4.5
0 + 0
0.2 _+ 0.2
0.8 -+ 0.3*
0 -+ 0
3.5 -+ 1.2
8.6 -+ 2.7
30 17.8 _+ 7.1 4.3 -+ 0.8* 27.7 -+ 6.5
* P < 0.05, compared with paracetamol alone.
188
45
60
120
31.0 -+ 7.4
45.8 -+ 6.2
100 +_ 0
11.8 -+ 2.3*
23.0 -+ 3,7"
72.8 -+ 8.1"
44.5 -+ 7.6
59.3 -+ 8.4
111.7 -+ 10.7
M. VAN WYK ET AL.
120
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O D <
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40
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20
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,
,
,
40
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,
,
60
,
I
80
,
~
,
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100
I
,
~
I
120
Time (min) Figure. M e a n values (n = 6) of t h e p e r c e n t of proportional c u m u l a t i v e area u n d e r t h e curve as a n index of gastric emptying. [ ] - - - [:3, P a r a c e t a m o l alone; * - - - * , p a r a c e t a m o l plus terbinafine; -~ -- - ÷ , paracetamol plus erythromycin.
stimulated acetylcholine release. 1° It is possible that similar explanations may be applied to terbinafine-induced gastric hypomotility.
Acknowledgment This study was supported in part by a research grant from the Medical 189
EFFECTSOFERYTHROMYCIN/TERBINAFINEONGASTRICEMPTYING
Research Council and the Department of Pharmacology, University of Pretoria, Pretoria, South Africa. References: 1. Ryder NS. The mechanism of action of terbinafine. ClinExpDermatol 1989; 14:98-100. 2. Villars V, Jones TC. Clinical efficacy and tolerability of terbinafine (Lamisil)--A new topical and systemic fungicidal drug for treatment of dermatomycoses. Clin Exp Dermatol 1989; 14:124-127. 3. Villars V, Jones TC. Present status of the efficacy and tolerability of terbinafine (Lamisil) used systemically in the treatment of dermatomycoses of the skin and nails. J Dermatol Treat 1990; l(Suppl 2):33-38. 4. Janssens J, Peeters TL, Vantrappen G, Tack J, et al. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. New Engl J Med 1990; 322:1028-1031. 5. Catnach SM, Fairclough PD. Review: Erythromycin and the gut. Gut 1992; 33:397-401. 6. Van Wyk M, Sommers De K, Snyman JR, Moncrieff J. A foreshortened method of measuring liquid gastric emptying in normal volunteers. Methods Find Exp Clin Pharmacol 1993; 15:61-66. 7. Vantrappen G. Erythromycin--The prokinetic drug of the future. Have we heard this story line before? Gastroenterology 1990; 99:559-568. 8. Zara GP, Qin XY, Pilot MA, et al. Erythromycin and gastrointestinal motility. Lancet 1987; 2:1036. 9. Depoortere I, Peeters TL, Vantrappen G. Erythromycin modulates motilin receptor density in rabbit. Gastroenterology 1989; 96:Al19. 10. Yau WM, Dorsett JA, Youther ML. Modulation of submucosal cholinergic neurons by 5-hydroxytryptamine and neuropeptides. Am J Physiol 1990; 259:G1019-G1024.
190