Eur J Clin Pharmacol (1990) 39:395-397
BQ[s oCeile@ © Springer-Verlag1990
The effect of exercise on atropine pharmacokinetics* G. H. K a m i m o r i 1, R. C. Smallridge 2, D. E R e d m o n d 1, G. L. B e l e n k y 1, and H. G. Fein 2 Department of Behavioral Biology and 2 Department of Clinical Physiology, Walter Reed Army Institute of Research, Washington, D. C. USA Received: June 16, 1990/Accepted: June 30, 1990
Summary. Seven healthy males (19-32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by R I A . Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the m e a n volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t,/2, 4.2 vs 3.5h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 m l - m i n -1) and significantly increased the p e a k concentration (Cp, 6.7 vs 12.3 ng. ml-1) and area under the curve ( A U C , 44.1 vs 53.1 ng-ml-1). In T5, Ex significantly decreased the tl/2 (3.4 h), Vz (182 1) and CL (575 ml. min ~) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min-~), elimination rate constant (ke, 0.0012 vs 0.0015 min-~), Cp (14 n g . m l 1) and A U C (53.3 ng. h- m l - 1). These results demonstrate that m o d e r a t e Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics. K e y words: atropine; exercise, pharmacokinetics, healthy volunteers
Atropine is an organic ester which functions as a competitive antagonist of acetylcholine [1]. Because of this property it is currently fielded by the U.S. military as a treatment for organophosphate poisoning. In order for a drug to produce its dynamic effects it must be present in appropriate concentrations. The combined influences of absorption, distribution, metabolism and excretion deter* Portions of this work were presented at the annual meeting of The American Society for Pharmacology and Experimental Therapeutics, Montreal, Canada, October 1988 The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the opinions of the Department of the Army or the Department of Defense.
mine drug concentrations at target tissues over time [2]. Changes in any of these parameters may result in a concurrent alteration in the dynamic effects of the drug as well as in its kinetics. Exercise is one variable which has been shown to influence the distribution and kinetics of some drugs in humans [1, 3, 4]. U n d e r field conditions it is reasonable to assume that military personnel will be involved in some form of physical activity either prior to or immediately following intramuscular administration of the drug. Although the kinetics [5] and dynamics [6] of atropine have been previously examined, the effects of exercise on the pharmacokinetics of the drug have yet to be examined in humans. Therefore, this study was designed to evaluate the effects of exercise, either prior to and or immediately following drug administration, on the pharmacokinetics of atropine sulfate in young men.
Materials and methods Seven healthy males (19-32 y) volunteered to participate in this study. All procedures were reviewed and approved by the Human Use Committee of the Walter Reed Army Institute of Research and the office of the Surgeon General of the Army. Prior to participation in the study, each subject completed a medical history and underwent a physical exam, glaucoma test, resting EKG and had his percent body fat determined by hydrostatic weighing [7]. In addition, each subject underwent a maximal exercise stress test on astationary cycle, to determine his maximal oxygen consumption (VO2 max). Each subject participated in each of four trials in an incomplete Latin square design to control for order effects and subjects were not informed as to whether they had received drug or placebo. In addition, 5 of the 7 subjects also completed a fifth trial which was differentiated as part II. Trials were administered at one week intervals. Characteristics of the subject populations for parts I and II are presented in Table 1. In all but T4, subjects received atropine sulfate (2.0 mg) as an intramuscular injection in the anterotateral portion of the left thigh. In T1, subjects received atropine and remained at rest for 12 h. In T2, subjects completed a single Ex bout prior to administration of atropine. In T3, the subjects received atropine followed immediately by three Ex bouts. In T5, subjects completed 25 min of cycling,rested in a seated position for 5 min, received atropine sulfate and immediately began an additional three Ex bouts. Each Ex bout consisted of stationary cycling at an intensity equal to 40% of the individual's VO2 max for 25 rain followed by a 5 rain seated rest. T4 was the same as T3 with the substitution of a saline placebo in place of the drug. In all trials subjects remained in a semi-reclining position when not engaged in exercise. The temperature in the test area ranged from 2124°C and humidity at approximately 60%. Trial outlines are presented in Table 2. Blood samples were collected 35 and 5 rain prior to drug administration and 1, 3, 5, 15, 30, 45, 60, 75, 90 min and 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, and 12 h following drug administration via an indwelling
396
G. H. Kamimori et al.: Exercise and atropine kinetics
Table 1. Characteristics of the subject population
Subject
Discussion
Age (y) 19 32 21 20 28 27 31
Weight (kg) 63.5 66.0 75.0 77.1 72.1 69.1 80.6
Body fat ~rO2max (%) (ml/kg/min) 9.4 54.7 10.9 54.7 9.3 44.1 15.5 42.9 11.6 60.3 15.4 35.8 16.2 38.2
go2
25 (5)
71.9 (6.1)
12.6 (3.0)
47.2 (13.2)
3350 (795)
Part II.(n = 5, sub 3-7) 25 74.8 (SD) (5) (4.4)
13.6 (3.0)
44.3 (9.6)
3150 (834)
1. 2. 3. 4. 5. 6. 7.
max
(ml) 3480 3480 3310 3310 4380 2480 2270
Part I. (n =7) (SD)
Table 2. Test trials
Drug - 30........ - 5 0...........25 30.........55 60.........86 90...........12 h
Time (rain) Trial rest 1 Rest rest 2 Exercise atropine 3 Atropine exercise 4 Placebo exercise 5 Atropine exercise atropine Exercise consisted of stationary cycling at 40% VO2 max. Drug or placebo was administered I. M. at time 0.
] ]
antecubital catheter. Patency of the catheter was maintained with a normal saline drip. Samples were allowed to clot, centrifuged at 2700 g for 15 min and serum was separated and stored at - 70°C. Analysis for serum atropine concentration was determined by radioimmunoassay using a previously described method [8]. Pharmacokinetic parameters were computed using PKCALC [9] for a one compartment model with first order kinetics. Statistical analysis consisted of an ANOVA for a repeated measures design with orthogonal contrasts for TI-T4 with n = 7. A separate ANOVA was run for T1 vs T5 with n = 5. The significance was set atp < 0.05.
T h e results of this study d e m o n s t r a t e that m o d e r a t e exercise (40% VO2 max), either i m m e d i a t e l y prior to or following the intramuscular administration of atropine, can m o d i f y the drug's pharmacokinetics. In the case of military applications it is m o s t i m p o r t a n t to deliver an antidote as quickly and in as high a concentration as possible in order to counteract the effect of a nerve agent [5]. T h e Cp increased in all exercise trials; however, this difference was only significant in T3 and T5. T h e Tp d e c r e a s e d in all three trials, but these differences were not statistically significant. In T2 the m e a n ka increased 39% while in T3 it d e c r e a s e d 17%. N e i t h e r of these differences were statistically significant. In T5, however, the ka was significantly increased by 98%, d e m o n s t r a t i n g that the c o m b i n a t i o n of E x b o t h prior to and following drug administration increased the relative rate of drug a b s o r p t i o n into the systemic circulation. M o d e r a t e exercise (40-65% VO2 max) has b e e n shown to result in an increase in cardiac output and systolic blood pressure [7, 11] as well as a dramatic increase in the perfusion rate of working muscle tissue [2, 11]. In this study, atropine sulfate was a d m i n i s t e r e d intramuscularly into the large portion of the quadriceps muscle. A n increased perfusion rate in the muscle following the initiation of E x could account for the increase in the ka seen in T2 (0.482 to 0.672 min-~). In T3, because no t~. Trial 1 z ~ - - z ~ Triat 2 • • Trial 3
15 p--n
E
10.
7:
,,-%&-.,_.
[d o K..
BQ[s oCeile@ © Springer-Verlag1990
The effect of exercise on atropine pharmacokinetics* G. H. K a m i m o r i 1, R. C. Smallridge 2, D. E R e d m o n d 1, G. L. B e l e n k y 1, and H. G. Fein 2 Department of Behavioral Biology and 2 Department of Clinical Physiology, Walter Reed Army Institute of Research, Washington, D. C. USA Received: June 16, 1990/Accepted: June 30, 1990
Summary. Seven healthy males (19-32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by R I A . Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the m e a n volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t,/2, 4.2 vs 3.5h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 m l - m i n -1) and significantly increased the p e a k concentration (Cp, 6.7 vs 12.3 ng. ml-1) and area under the curve ( A U C , 44.1 vs 53.1 ng-ml-1). In T5, Ex significantly decreased the tl/2 (3.4 h), Vz (182 1) and CL (575 ml. min ~) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min-~), elimination rate constant (ke, 0.0012 vs 0.0015 min-~), Cp (14 n g . m l 1) and A U C (53.3 ng. h- m l - 1). These results demonstrate that m o d e r a t e Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics. K e y words: atropine; exercise, pharmacokinetics, healthy volunteers
Atropine is an organic ester which functions as a competitive antagonist of acetylcholine [1]. Because of this property it is currently fielded by the U.S. military as a treatment for organophosphate poisoning. In order for a drug to produce its dynamic effects it must be present in appropriate concentrations. The combined influences of absorption, distribution, metabolism and excretion deter* Portions of this work were presented at the annual meeting of The American Society for Pharmacology and Experimental Therapeutics, Montreal, Canada, October 1988 The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the opinions of the Department of the Army or the Department of Defense.
mine drug concentrations at target tissues over time [2]. Changes in any of these parameters may result in a concurrent alteration in the dynamic effects of the drug as well as in its kinetics. Exercise is one variable which has been shown to influence the distribution and kinetics of some drugs in humans [1, 3, 4]. U n d e r field conditions it is reasonable to assume that military personnel will be involved in some form of physical activity either prior to or immediately following intramuscular administration of the drug. Although the kinetics [5] and dynamics [6] of atropine have been previously examined, the effects of exercise on the pharmacokinetics of the drug have yet to be examined in humans. Therefore, this study was designed to evaluate the effects of exercise, either prior to and or immediately following drug administration, on the pharmacokinetics of atropine sulfate in young men.
Materials and methods Seven healthy males (19-32 y) volunteered to participate in this study. All procedures were reviewed and approved by the Human Use Committee of the Walter Reed Army Institute of Research and the office of the Surgeon General of the Army. Prior to participation in the study, each subject completed a medical history and underwent a physical exam, glaucoma test, resting EKG and had his percent body fat determined by hydrostatic weighing [7]. In addition, each subject underwent a maximal exercise stress test on astationary cycle, to determine his maximal oxygen consumption (VO2 max). Each subject participated in each of four trials in an incomplete Latin square design to control for order effects and subjects were not informed as to whether they had received drug or placebo. In addition, 5 of the 7 subjects also completed a fifth trial which was differentiated as part II. Trials were administered at one week intervals. Characteristics of the subject populations for parts I and II are presented in Table 1. In all but T4, subjects received atropine sulfate (2.0 mg) as an intramuscular injection in the anterotateral portion of the left thigh. In T1, subjects received atropine and remained at rest for 12 h. In T2, subjects completed a single Ex bout prior to administration of atropine. In T3, the subjects received atropine followed immediately by three Ex bouts. In T5, subjects completed 25 min of cycling,rested in a seated position for 5 min, received atropine sulfate and immediately began an additional three Ex bouts. Each Ex bout consisted of stationary cycling at an intensity equal to 40% of the individual's VO2 max for 25 rain followed by a 5 rain seated rest. T4 was the same as T3 with the substitution of a saline placebo in place of the drug. In all trials subjects remained in a semi-reclining position when not engaged in exercise. The temperature in the test area ranged from 2124°C and humidity at approximately 60%. Trial outlines are presented in Table 2. Blood samples were collected 35 and 5 rain prior to drug administration and 1, 3, 5, 15, 30, 45, 60, 75, 90 min and 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, and 12 h following drug administration via an indwelling
396
G. H. Kamimori et al.: Exercise and atropine kinetics
Table 1. Characteristics of the subject population
Subject
Discussion
Age (y) 19 32 21 20 28 27 31
Weight (kg) 63.5 66.0 75.0 77.1 72.1 69.1 80.6
Body fat ~rO2max (%) (ml/kg/min) 9.4 54.7 10.9 54.7 9.3 44.1 15.5 42.9 11.6 60.3 15.4 35.8 16.2 38.2
go2
25 (5)
71.9 (6.1)
12.6 (3.0)
47.2 (13.2)
3350 (795)
Part II.(n = 5, sub 3-7) 25 74.8 (SD) (5) (4.4)
13.6 (3.0)
44.3 (9.6)
3150 (834)
1. 2. 3. 4. 5. 6. 7.
max
(ml) 3480 3480 3310 3310 4380 2480 2270
Part I. (n =7) (SD)
Table 2. Test trials
Drug - 30........ - 5 0...........25 30.........55 60.........86 90...........12 h
Time (rain) Trial rest 1 Rest rest 2 Exercise atropine 3 Atropine exercise 4 Placebo exercise 5 Atropine exercise atropine Exercise consisted of stationary cycling at 40% VO2 max. Drug or placebo was administered I. M. at time 0.
] ]
antecubital catheter. Patency of the catheter was maintained with a normal saline drip. Samples were allowed to clot, centrifuged at 2700 g for 15 min and serum was separated and stored at - 70°C. Analysis for serum atropine concentration was determined by radioimmunoassay using a previously described method [8]. Pharmacokinetic parameters were computed using PKCALC [9] for a one compartment model with first order kinetics. Statistical analysis consisted of an ANOVA for a repeated measures design with orthogonal contrasts for TI-T4 with n = 7. A separate ANOVA was run for T1 vs T5 with n = 5. The significance was set atp < 0.05.
T h e results of this study d e m o n s t r a t e that m o d e r a t e exercise (40% VO2 max), either i m m e d i a t e l y prior to or following the intramuscular administration of atropine, can m o d i f y the drug's pharmacokinetics. In the case of military applications it is m o s t i m p o r t a n t to deliver an antidote as quickly and in as high a concentration as possible in order to counteract the effect of a nerve agent [5]. T h e Cp increased in all exercise trials; however, this difference was only significant in T3 and T5. T h e Tp d e c r e a s e d in all three trials, but these differences were not statistically significant. In T2 the m e a n ka increased 39% while in T3 it d e c r e a s e d 17%. N e i t h e r of these differences were statistically significant. In T5, however, the ka was significantly increased by 98%, d e m o n s t r a t i n g that the c o m b i n a t i o n of E x b o t h prior to and following drug administration increased the relative rate of drug a b s o r p t i o n into the systemic circulation. M o d e r a t e exercise (40-65% VO2 max) has b e e n shown to result in an increase in cardiac output and systolic blood pressure [7, 11] as well as a dramatic increase in the perfusion rate of working muscle tissue [2, 11]. In this study, atropine sulfate was a d m i n i s t e r e d intramuscularly into the large portion of the quadriceps muscle. A n increased perfusion rate in the muscle following the initiation of E x could account for the increase in the ka seen in T2 (0.482 to 0.672 min-~). In T3, because no t~. Trial 1 z ~ - - z ~ Triat 2 • • Trial 3
15 p--n
E
10.
7:
,,-%&-.,_.
[d o K..
