Eur J Clin Pharmacol (1992) 42:40%412 EuropeanJ..... I of ( ~ [ ] ~ ( ~ @ [ ]
@Springer-Verlag 1992
The influence of levodopa on gastric emptying in healthy elderly volunteers D. R. C. R o b e r t s o n 1, A. G. R e n w i c k 2, B. Macklin 2, S. Jones 2, D. G. Waller 2, C. E G e o r g e 2, and J. S. Fleming 3
Geriatric Medicine:, ClinicalPharmacology2, and Nuclear Medicine3,University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO9 4XY Received: February 12, 1991/Accepted in revised form: September 16, 1991
Summary. Paracetamol absorption and 99Tc-DTPA meas-
urements have been used to determine the influence of levodopa on gastric emptying in 8 healthy elderly volunteers. In the absence of levodopa 7 subjects showed a rapid gastric emptying pattern by gamma-camera and a single major peak in the plasma concentration-time curve of paracetamol. One subject showed two rapid phases of gastric emptying separated by a period of negligible emptying and had 2 separate peaks in the paracetamol plasma concentration-time curve. In the presence of levodopa, the gamma-camera data for 6 subjects showed a pattern of gastric emptying consisting of 2 rapid phases separated by a plateau. In each case secondary peaks in the plasma concentration-time curve of paracetamol occurred about 30 rain after the end of the plateau. The time to 90 % emptying on the gamma scan was increased significantly from 40 min to 65 min in the presence of levodopa. Comparison of the present data with those reported previously indicates that levodopa affects gastric emptying in the both elderly and young volunteers to a similar extent. Key words: Levodopa, Gastric emptying; paracetamol,
elderly subjects
Robertson et al. 1989] could contribute to fluctuations in response. The multiple plasma peaks arise from an effect of levodopa on the pattern of gastric emptying [Robertson et al. 1990]. Both levodopa and paracetamol are absorbed rapidly from the small intestine and their absorption is dependent on gastric emptying [Robertson et al. 1990]. Coincident double plasma peaks of both levodopa and paracetamol were found in 6 out of 8 young volunteers given levodopa, paracetamol and 99Tc-DTPA simultaneously. Using paracetamol and gamma camera imaging as markers of gastric emptying the double peaks were shown to coincide with 2 distinct phases of gastric emptying, separated by a period without appreciable emptying [Robertson et al. 1990]. Parkinson's disease is primarily a condition of the elderly, and prolonged liquid gastric emptying has been reported in healthy elderly subjects [Moore et al. 1983; Horowitz et al. 1984]. Bortolotti et al. (1987) observed abnormal inter-digestive gastric motility in elderly subjects with reduced phase-3 activity of the migratory motor complex. Therefore the effects of levodopa on gastric emptying in young volunteers may not be predictive for elderly patients. This possibility has been investigated by undertaking a study on the influence of levodopa on gastric emptying in healthy elderly subjects.
Methods
Levodopa has become the mainstay of treatment for Parkinson's disease; but as the disease progresses, the problem of fluctuating clinical response becomes increasingly frequent. It is believed to be related to a reduced ability to store dopamine centrally so that the patient is more dependent on continued synthesis from levodopa. Maintenance of a constant plasma concentration of levodopa by intravenous or intraduodenal infusion has been shown to produce a stable clinical response [Quinn et al. 1984; Kurlan et al. 1986, 1988; Sage et al. 1988]. Therefore multiple peak plasma concentrations of levodopa observed following a single oral dose [Evans et al. 1981 a; Wade et al. 1974;
The study was approved by the local Ethics Committee and all subjects gave written informed consent. Eight elderly male subjects were recruited from a register of healthy elderly volunteers (mean age 73 y) (range 65-78 y). The mean body weight (78.8 kg; range 7190 kg) was similar to that of the young volunteers (74.8 kg) studied previously [Robertson et al. 1990].None of the volunteers had a history of gastrointestinal disease. Only one subject was receiving medication (digoxin and warfarin) and these were not taken on the morning of the study. One of the volunteers was a smoker, but he refrained from smoking for two weeks prior to the study.The subjects were studied after an overnight fast on 2 occasions separated by an interval of one week. The protocol was identical to that described previouslyfor young volunteers [Robertson et al. 1990].In summary
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signed rank test for comparisons within the elderly volunteers and by rank-sum test for comparisons of the data in elderly (this paper) and young volunteers [Robertson et al. 1990]. The initial phase of gastric emptying determined by gamma camera imaging was analysed by log-linear least squares regression and the half-life of emptying derived from the rate constant. The time to the end of the plateau phase detected in some studies was determined by visual inspection of the data (see Fig. 1-3).
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Following administration of paracetamol and D T P A on the control day, 7 of the 8 subjects showed rapid gastric emptying and a single major p e a k on the paracetamol plasma concentration-time curve (Fig. 1). The half life for the initial phase of gastric emptying was 9 (4) min and the time to 90 % emptying was 40 (17) rain. The individual who had the highest ti value for paracetamol showed an 18 min lag phase on the g a m m a - c a m e r a scan prior to the start of rapid gastric emptying. Only 1 subject showed a clear plateau on the g a m m a - c a m e r a scan indicating an interruption in gastric emptying. This occurred between 30 and 58 rain after the dose and was associated with a secondary peak on the paracetamol plasma concentrationtime curve at 75 min (Fig. 2).
Fig. 1. The influence of levodopa on gastric emptying in an elderly volunteer. Similar profiles, with a single phase of emptying and a single peak concentration of paracetamol in plasma, were found in 7 subjects on the control day. In contrast, 2 phases of emptying and 2 peak plasma concentrations of paracetamol were found in 6 subjects following levodopa (as indicated in the right hand panels), top panels: gamma camera gastric emptying profiles; bottompanels: plasma concentration-time curves for paracetamol; left-hand panels: data for the day when only 99Tc-DTPAand paracetamol were given; right-hand panels: data for the day when 99Tc-DTPA,paracetamol and levodopa were co-administered
the subjects received in random order a solution containing 99TcDTPA (12MBq) and soluble paracetamol (1.5 g) in 100 ml water on one occasion and a solution containing 99Tc-DTPA (12 MBq), soluble paracetamol (1.5 g) and levodopa (125 mg) in 100 ml of water on the other occasion. Carbidopa (100 mg) was given as tablets 1 h prior to the dose on each occasion. The subjects remained semi-recumbent for 4 h after the dose and were then given a standard lunch containing 25 g of protein. Gastric emptying was determined by serial scintigraphy with a gamma camera [Fleming et al. 1987] and the concentrations of paracetamol measured in plasma samples collected prior to and at frequent intervals after the dose (10, 20, 30, 40, 50, 60, 75, 90,105,120,135,150, 165,180,240,360 and 480 rain) using a published method [Ameer et al. 1981].
Pharmacokinetic analysis The concentration of the initial plasma peak (C~) and the time of C~ (t~) are the observed values. The area under the plasma concentration-time curve (AUC) was calculated by the trapezoidal rule with extrapolation to infinity as described by Gibaldi and Perrier (1982). Since the paracetamol assay had a coefficient of variation of approximately _+5 % we defined a "peak" in the plasma concentration-time curve as a rise in plasma concentration of > 10%. Results are expressed as mean with (SD). Statistical analysis was by Wilcoxon's
Gastric emptying and paracetamol absorption when co-administered with levodopa In contrast, when levodopa was given with paracetamol and DTPA, both the half-life of initial emptying (28(47) min) and the time to 90 % emptying (65(23) rain) were increased, the latter achieving statistical significance (P < 0.05). Six out of the 8 subjects showed a pronounced plateau phase on the g a m m a - c a m e r a scan. The time courses for these were similar in all 6 subjects with the plateau phase starting 16-34 min after dosing and lasting for an average of 39 min (33-43 min) (Table 1). In all cases the plasma concentration-time curves for paracetamol were consistent with the g a m m a - c a m e r a data with secondary p e a k concentrations occurring about 30 min after the end of the plateau on the scan (Fig. 1-3). Coadministration of levodopa did not alter any other pharmacokinetic p a r a m e t e r of paracetamol (Table 1). The shape of the plasma concentration-time curve of paracetamol was dependent on the extent of gastric emptying prior to the start of the plateau on the gamma-scan. For example the subject in Fig. 3 showed limited gastric emptying prior to the plateau so that the post-plateau p e a k of paracetamol was considerably higher than earlier concentrations. This contrasts with the subjects in Fig. 1 and 2 who emptied more than 50 % of their stomach contents prior to the plateau on the gamma-scan so that the post-plateau peaks of paracetamol were similar to or lower than the initial peaks. Two subjects did not show a plateau on the gammacamera scan in the presence of levodopa and neither of these subjects showed a pattern of multiple peaks in the paracetamol plasma concentration-time curve.
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cant age related differences in gastric emptying as indicated by initial emptying half-life or the time to 90 % emptying from the gamma camera data (Table 1). In both age groups coadministration of levodopa caused an approximately 3 fold increase in the half-life of initial emptying and a significant prolongation of the time to 90 % emptying. Similar numbers of subjects in each age group showed a plateau on their gamma-camera scans and secondary peaks in the paracetamol plasma-concentration time curves. Thus, overall the plasma concentration-time curves for paracetamol were similar in both age groups. Although the effect of levodopa on Ci of paracetamol was statistically significant in the young it did not achieve statistical significance in the elderly by signed rank test but was just significant by Student's t-test for paired data (P = 0.05).
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Fig. 2. The pattern of gastric emptying in the single elderly volunteer who showed 2 phases of gastric emptying and two peak plasma concentrations of paracetamol on the control day. top panels: gamma camera gastric emptying profiles; bottom panels: plasma concentration-time curves for paracetamol; left-handpanels: data for the day when only 99Tc-DTPAand paracetamol were given; right-handpanels: data for the day when 99Tc-DTPA,paracetamol and levodopa were co-administered
Comparison of the effects of levodopa on gastric emptying in elderly and young volunteers Comparison of the present data for the control day in elderly volunteers with the results of the previous study in young subjects [Robertson et al. 1990] showed no signifi-
The results of the present study indicate that the effects of levodopa on gastric emptying in elderly subjects are similar to those seen in young volunteers [Robertson et al. 1990]. Following administration of levodopa, 6 of the 8 volunteers studied showed 2 distinct phases of gastric emptying separated by a plateau of limited or negligible emptying. The incidence and duration of the plateaux were similar to those found in young subjects. There were wide inter-individual variations in the resulting plasma concentration-time curves for paracetamol comparable to those found in young subjects given levodopa and paracetamol. These data indicate that elderly subjects show a similar response to the gastrointestinal effects of oral doses of levodopa. The initial gastric emptying half-lives on the control day in both elderly and young groups (Table 1) were consistent with recent publications [Horowitz et al. 1984; Kupfer et al. 1985; Rashid and Bateman 1990] of which only one [Horowitz et al. 1984] reported significantly slower emptying in the elderly. The earlier report of a greatly prolonged half-life of gastric emptying in elderly
Table 1. The effects of levodopa on gastric emptying and the plasma concentration-time curve of paracetamol
Gamma-camera data Initial emptying half-life (min) Presence of plateau (n) a Duration of plateau (min) Time to 90 % emptying (min) Paracetamol data Ci (btg.m1-1) ti (min) AUC (pg-ml-1. h) Multiple peaks (n)"
Elderly without levodopa
with levodopa
Young without levodopa
with levodopa
9 (4) 1 28 40 (17)
28 (47) 6 39 (5) 65 (23)*
6 (3) 0 32 (24)
16 (10)* 6 43 (9) 81 (20)**
32.7 (8.5) 28 (7) 83.3 (13.3) 1
25.6 (11.3) 24 (5) 76.4 (14.0) 6
33.1 (11.0) 23 (11) 76.2 (10.5) 0
24.2 (6.5)* 28 (19) 77.8 (13.7) 6
The data are means with (SD) for 8 individuals. Data for young healthy volunteers from Robertson et al. (1990) a number of subjects showing a plateau on the gamma-scan or multiple peaks in the concentration-time curve * P < 0.05 compared with control day (without levodopa) in the same age group by ** P < 0.01 signed rank test. No significant age related differences were detected by rank sum test
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Roche Products Ltd for levodopa, and to Merck, Sharp and Dohme Ltd for carbidopa tablets. t
References
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Fig. 3. The influence of levodopa on gastric emptying in an elderly volunteer, top panels: gamma camera gastric emptying profiles; bottom panels: plasma concentration-time curves for paracetamol; lefthandpanels: data for the day when only 99Tc-DTPAand paracetamol were given; right-hand panels: data for the day when 99Tc-DTPA, paracetamol and levodopa were co-administered. The apparent second peak in the paracetamol curve on the control day represents only a 6 % increase and therefore could have arisen from measurement errors
patients [123 min; E v a n s et al. 1981b] m a y have arisen from the chronic multiple pathologies in the patients studied and the supine posture a d o p t e d during measurements. T h e Ci and ti values for p a r a c e t a m o l on the control day given in Table 1 are consistent with the absence of any age related difference in gastric emptying. T h e effects of l e v o d o p a on gastric emptying in elderly volunteers provide a m e c h a n i s m for the multiple p e a k plasma concentrations detected in elderly subjects following a single oral dose of l e v o d o p a [ R o b e r t s o n et al. 1989]. Such peaks could contribute to the fluctuating response in elderly patients with a d v a n c e d Parkinson's disease, in w h o m the clinical benefit b e c o m e s increasingly dependent u p o n delivery of l e v o d o p a to the striatum [Nutt 1987]. Thus attempts to p r o d u c e a m o r e consistent clinical response by the frequent administration of small doses m a y be limited b y cumulative effects on gastric emptying with erratic delivery of subsequent doses to the site of absorption.
Acknowledgements. We are grateful to the British Medical Association for financial support through the Doris Hillier Award, to
Ameer B, Greenblatt DJ, Divoll M, Abernethy DR, Shargel L (1981) High performance liquid chromatographic determination of acetaminophen in plasma: single-dose pharmacokinetic studies. J Chromatogr 226:224-230 Bortolotti M, Frada G, Vezzadini R Bonora G, Barbagallo-Sangiorgi G, Labo G (1987) Influence of gastric acid secretion on interdigestive gastric motor activity and serum motilin in the elderly. Digestion 38:226-233 Evans MA, Broe GA, Triggs E J, Cheung M, Creasey H, Paull PD (1981 a) Gastric emptyingrate and the systemic availability oflevodopa in the elderly Parkinsonian patient. Neurology 31:1288-1294 Evans MA, Triggs EJ, Cheung M, Broe GA, Creasey H (1981b) Gastric emptying rate in the elderly: implications for drug therapy. J Am Geriatr Soc 29:201-205 Fleming JS, Britten AJ, Blake GM, Gray J, Howlett PJ (1987) A general software system for the handling of medical images. Nucl Med Comm 8:270 Gibaldi M, Perrier D (1982) Pharmacokinetics, (2rid edn revised and expanded). Marcel Dekker, New York Horowitz M, Maddern G J, Chatterton BE, Collins PJ, Harding PE, Shearman DJC (1984) Changes in gastric emptying rates with age. Clin Sci 67:213-218 Kupfer RM, HeppelI M, Haggith JW, Bateman DN (1985) Gastric emptying and small-bowel transit rate in the elderly. J Am Geriatr Soc 33:340-343 Kurlan R, Rubin AJ, Miller C, Rivera-Calimlim L, Clarke A, Shoulson I (1986) Duodenal delivery of levodopa for on-offfluctuations in Parkinsonism: Preliminary Observations. Ann Neuro120: 262264 Kurlan R, Rothfleld KP, Woodward WR, Nutt JG, Miller C, Lichter D, Shoulson I (1988) Erratic gastric emptying of levodopa may cause "random" fluctuations of Parkinsonian mobility. Neurology 38:41%421 Moore JG, Tweedy C, Christian PE, Datz FL (1983) Effect of age on gastric emptying of liquid-solid meals in man. Dig Dis Sci 28: 340344 Nutt JG (1987) On-off phenomenon: relation to levodopa pliarmacokinetics and pharmacodynamics. Ann Neuro122:535-540 Quinn N, Parkes JD, Marsden CD (1984) Control of on/off phenomenon by continuous intravenous infusion of ievodopa. Neurology 34:1131-1136 Rashid MV, Bateman DN (1990) Effect of intravenous atropine on gastric emptying, paracetamol absorption, salivary flow and heart rate in young and fit elderly volunteers. Br J Clin Pharmacol 30: 25-34 Robertson DRC, Wood ND, Everest H, Monks K, Waller D G, Renwick AG, George CF (1989) The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmaco128:61-69 Robertson DRC, Renwick AG, Wood ND, Cross N, Macklin BS, Fleming JS, Waller DG, George CF (1990) The influence of levodopa on gastric emptying in man. Br J Clin Pharmaco129:47-53 Sage JI, Schuh L, Heikkila RE, Duvoisin RC (1988) Continuous duodenal infusions of levodopa: plasma concentrations and motor fluctuations in Parkinson's disease. Clin Neuro-Pharmaco111: 3644 Wade DN, Mearrick PT, Birkett D J, Morris J (1974) Variability of 1-dopa absorption in man. Aust NZ J Med 4:138-143 Dr. A. G. Renwick Clinical Pharmacology Group University of Southampton Medical and Biological Sciences Building Bassett Crescent East Southampton SO9 3TU, UK
@Springer-Verlag 1992
The influence of levodopa on gastric emptying in healthy elderly volunteers D. R. C. R o b e r t s o n 1, A. G. R e n w i c k 2, B. Macklin 2, S. Jones 2, D. G. Waller 2, C. E G e o r g e 2, and J. S. Fleming 3
Geriatric Medicine:, ClinicalPharmacology2, and Nuclear Medicine3,University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO9 4XY Received: February 12, 1991/Accepted in revised form: September 16, 1991
Summary. Paracetamol absorption and 99Tc-DTPA meas-
urements have been used to determine the influence of levodopa on gastric emptying in 8 healthy elderly volunteers. In the absence of levodopa 7 subjects showed a rapid gastric emptying pattern by gamma-camera and a single major peak in the plasma concentration-time curve of paracetamol. One subject showed two rapid phases of gastric emptying separated by a period of negligible emptying and had 2 separate peaks in the paracetamol plasma concentration-time curve. In the presence of levodopa, the gamma-camera data for 6 subjects showed a pattern of gastric emptying consisting of 2 rapid phases separated by a plateau. In each case secondary peaks in the plasma concentration-time curve of paracetamol occurred about 30 rain after the end of the plateau. The time to 90 % emptying on the gamma scan was increased significantly from 40 min to 65 min in the presence of levodopa. Comparison of the present data with those reported previously indicates that levodopa affects gastric emptying in the both elderly and young volunteers to a similar extent. Key words: Levodopa, Gastric emptying; paracetamol,
elderly subjects
Robertson et al. 1989] could contribute to fluctuations in response. The multiple plasma peaks arise from an effect of levodopa on the pattern of gastric emptying [Robertson et al. 1990]. Both levodopa and paracetamol are absorbed rapidly from the small intestine and their absorption is dependent on gastric emptying [Robertson et al. 1990]. Coincident double plasma peaks of both levodopa and paracetamol were found in 6 out of 8 young volunteers given levodopa, paracetamol and 99Tc-DTPA simultaneously. Using paracetamol and gamma camera imaging as markers of gastric emptying the double peaks were shown to coincide with 2 distinct phases of gastric emptying, separated by a period without appreciable emptying [Robertson et al. 1990]. Parkinson's disease is primarily a condition of the elderly, and prolonged liquid gastric emptying has been reported in healthy elderly subjects [Moore et al. 1983; Horowitz et al. 1984]. Bortolotti et al. (1987) observed abnormal inter-digestive gastric motility in elderly subjects with reduced phase-3 activity of the migratory motor complex. Therefore the effects of levodopa on gastric emptying in young volunteers may not be predictive for elderly patients. This possibility has been investigated by undertaking a study on the influence of levodopa on gastric emptying in healthy elderly subjects.
Methods
Levodopa has become the mainstay of treatment for Parkinson's disease; but as the disease progresses, the problem of fluctuating clinical response becomes increasingly frequent. It is believed to be related to a reduced ability to store dopamine centrally so that the patient is more dependent on continued synthesis from levodopa. Maintenance of a constant plasma concentration of levodopa by intravenous or intraduodenal infusion has been shown to produce a stable clinical response [Quinn et al. 1984; Kurlan et al. 1986, 1988; Sage et al. 1988]. Therefore multiple peak plasma concentrations of levodopa observed following a single oral dose [Evans et al. 1981 a; Wade et al. 1974;
The study was approved by the local Ethics Committee and all subjects gave written informed consent. Eight elderly male subjects were recruited from a register of healthy elderly volunteers (mean age 73 y) (range 65-78 y). The mean body weight (78.8 kg; range 7190 kg) was similar to that of the young volunteers (74.8 kg) studied previously [Robertson et al. 1990].None of the volunteers had a history of gastrointestinal disease. Only one subject was receiving medication (digoxin and warfarin) and these were not taken on the morning of the study. One of the volunteers was a smoker, but he refrained from smoking for two weeks prior to the study.The subjects were studied after an overnight fast on 2 occasions separated by an interval of one week. The protocol was identical to that described previouslyfor young volunteers [Robertson et al. 1990].In summary
410 50,000
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signed rank test for comparisons within the elderly volunteers and by rank-sum test for comparisons of the data in elderly (this paper) and young volunteers [Robertson et al. 1990]. The initial phase of gastric emptying determined by gamma camera imaging was analysed by log-linear least squares regression and the half-life of emptying derived from the rate constant. The time to the end of the plateau phase detected in some studies was determined by visual inspection of the data (see Fig. 1-3).
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Following administration of paracetamol and D T P A on the control day, 7 of the 8 subjects showed rapid gastric emptying and a single major p e a k on the paracetamol plasma concentration-time curve (Fig. 1). The half life for the initial phase of gastric emptying was 9 (4) min and the time to 90 % emptying was 40 (17) rain. The individual who had the highest ti value for paracetamol showed an 18 min lag phase on the g a m m a - c a m e r a scan prior to the start of rapid gastric emptying. Only 1 subject showed a clear plateau on the g a m m a - c a m e r a scan indicating an interruption in gastric emptying. This occurred between 30 and 58 rain after the dose and was associated with a secondary peak on the paracetamol plasma concentrationtime curve at 75 min (Fig. 2).
Fig. 1. The influence of levodopa on gastric emptying in an elderly volunteer. Similar profiles, with a single phase of emptying and a single peak concentration of paracetamol in plasma, were found in 7 subjects on the control day. In contrast, 2 phases of emptying and 2 peak plasma concentrations of paracetamol were found in 6 subjects following levodopa (as indicated in the right hand panels), top panels: gamma camera gastric emptying profiles; bottompanels: plasma concentration-time curves for paracetamol; left-hand panels: data for the day when only 99Tc-DTPAand paracetamol were given; right-hand panels: data for the day when 99Tc-DTPA,paracetamol and levodopa were co-administered
the subjects received in random order a solution containing 99TcDTPA (12MBq) and soluble paracetamol (1.5 g) in 100 ml water on one occasion and a solution containing 99Tc-DTPA (12 MBq), soluble paracetamol (1.5 g) and levodopa (125 mg) in 100 ml of water on the other occasion. Carbidopa (100 mg) was given as tablets 1 h prior to the dose on each occasion. The subjects remained semi-recumbent for 4 h after the dose and were then given a standard lunch containing 25 g of protein. Gastric emptying was determined by serial scintigraphy with a gamma camera [Fleming et al. 1987] and the concentrations of paracetamol measured in plasma samples collected prior to and at frequent intervals after the dose (10, 20, 30, 40, 50, 60, 75, 90,105,120,135,150, 165,180,240,360 and 480 rain) using a published method [Ameer et al. 1981].
Pharmacokinetic analysis The concentration of the initial plasma peak (C~) and the time of C~ (t~) are the observed values. The area under the plasma concentration-time curve (AUC) was calculated by the trapezoidal rule with extrapolation to infinity as described by Gibaldi and Perrier (1982). Since the paracetamol assay had a coefficient of variation of approximately _+5 % we defined a "peak" in the plasma concentration-time curve as a rise in plasma concentration of > 10%. Results are expressed as mean with (SD). Statistical analysis was by Wilcoxon's
Gastric emptying and paracetamol absorption when co-administered with levodopa In contrast, when levodopa was given with paracetamol and DTPA, both the half-life of initial emptying (28(47) min) and the time to 90 % emptying (65(23) rain) were increased, the latter achieving statistical significance (P < 0.05). Six out of the 8 subjects showed a pronounced plateau phase on the g a m m a - c a m e r a scan. The time courses for these were similar in all 6 subjects with the plateau phase starting 16-34 min after dosing and lasting for an average of 39 min (33-43 min) (Table 1). In all cases the plasma concentration-time curves for paracetamol were consistent with the g a m m a - c a m e r a data with secondary p e a k concentrations occurring about 30 min after the end of the plateau on the scan (Fig. 1-3). Coadministration of levodopa did not alter any other pharmacokinetic p a r a m e t e r of paracetamol (Table 1). The shape of the plasma concentration-time curve of paracetamol was dependent on the extent of gastric emptying prior to the start of the plateau on the gamma-scan. For example the subject in Fig. 3 showed limited gastric emptying prior to the plateau so that the post-plateau p e a k of paracetamol was considerably higher than earlier concentrations. This contrasts with the subjects in Fig. 1 and 2 who emptied more than 50 % of their stomach contents prior to the plateau on the gamma-scan so that the post-plateau peaks of paracetamol were similar to or lower than the initial peaks. Two subjects did not show a plateau on the gammacamera scan in the presence of levodopa and neither of these subjects showed a pattern of multiple peaks in the paracetamol plasma concentration-time curve.
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cant age related differences in gastric emptying as indicated by initial emptying half-life or the time to 90 % emptying from the gamma camera data (Table 1). In both age groups coadministration of levodopa caused an approximately 3 fold increase in the half-life of initial emptying and a significant prolongation of the time to 90 % emptying. Similar numbers of subjects in each age group showed a plateau on their gamma-camera scans and secondary peaks in the paracetamol plasma-concentration time curves. Thus, overall the plasma concentration-time curves for paracetamol were similar in both age groups. Although the effect of levodopa on Ci of paracetamol was statistically significant in the young it did not achieve statistical significance in the elderly by signed rank test but was just significant by Student's t-test for paired data (P = 0.05).
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Fig. 2. The pattern of gastric emptying in the single elderly volunteer who showed 2 phases of gastric emptying and two peak plasma concentrations of paracetamol on the control day. top panels: gamma camera gastric emptying profiles; bottom panels: plasma concentration-time curves for paracetamol; left-handpanels: data for the day when only 99Tc-DTPAand paracetamol were given; right-handpanels: data for the day when 99Tc-DTPA,paracetamol and levodopa were co-administered
Comparison of the effects of levodopa on gastric emptying in elderly and young volunteers Comparison of the present data for the control day in elderly volunteers with the results of the previous study in young subjects [Robertson et al. 1990] showed no signifi-
The results of the present study indicate that the effects of levodopa on gastric emptying in elderly subjects are similar to those seen in young volunteers [Robertson et al. 1990]. Following administration of levodopa, 6 of the 8 volunteers studied showed 2 distinct phases of gastric emptying separated by a plateau of limited or negligible emptying. The incidence and duration of the plateaux were similar to those found in young subjects. There were wide inter-individual variations in the resulting plasma concentration-time curves for paracetamol comparable to those found in young subjects given levodopa and paracetamol. These data indicate that elderly subjects show a similar response to the gastrointestinal effects of oral doses of levodopa. The initial gastric emptying half-lives on the control day in both elderly and young groups (Table 1) were consistent with recent publications [Horowitz et al. 1984; Kupfer et al. 1985; Rashid and Bateman 1990] of which only one [Horowitz et al. 1984] reported significantly slower emptying in the elderly. The earlier report of a greatly prolonged half-life of gastric emptying in elderly
Table 1. The effects of levodopa on gastric emptying and the plasma concentration-time curve of paracetamol
Gamma-camera data Initial emptying half-life (min) Presence of plateau (n) a Duration of plateau (min) Time to 90 % emptying (min) Paracetamol data Ci (btg.m1-1) ti (min) AUC (pg-ml-1. h) Multiple peaks (n)"
Elderly without levodopa
with levodopa
Young without levodopa
with levodopa
9 (4) 1 28 40 (17)
28 (47) 6 39 (5) 65 (23)*
6 (3) 0 32 (24)
16 (10)* 6 43 (9) 81 (20)**
32.7 (8.5) 28 (7) 83.3 (13.3) 1
25.6 (11.3) 24 (5) 76.4 (14.0) 6
33.1 (11.0) 23 (11) 76.2 (10.5) 0
24.2 (6.5)* 28 (19) 77.8 (13.7) 6
The data are means with (SD) for 8 individuals. Data for young healthy volunteers from Robertson et al. (1990) a number of subjects showing a plateau on the gamma-scan or multiple peaks in the concentration-time curve * P < 0.05 compared with control day (without levodopa) in the same age group by ** P < 0.01 signed rank test. No significant age related differences were detected by rank sum test
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Fig. 3. The influence of levodopa on gastric emptying in an elderly volunteer, top panels: gamma camera gastric emptying profiles; bottom panels: plasma concentration-time curves for paracetamol; lefthandpanels: data for the day when only 99Tc-DTPAand paracetamol were given; right-hand panels: data for the day when 99Tc-DTPA, paracetamol and levodopa were co-administered. The apparent second peak in the paracetamol curve on the control day represents only a 6 % increase and therefore could have arisen from measurement errors
patients [123 min; E v a n s et al. 1981b] m a y have arisen from the chronic multiple pathologies in the patients studied and the supine posture a d o p t e d during measurements. T h e Ci and ti values for p a r a c e t a m o l on the control day given in Table 1 are consistent with the absence of any age related difference in gastric emptying. T h e effects of l e v o d o p a on gastric emptying in elderly volunteers provide a m e c h a n i s m for the multiple p e a k plasma concentrations detected in elderly subjects following a single oral dose of l e v o d o p a [ R o b e r t s o n et al. 1989]. Such peaks could contribute to the fluctuating response in elderly patients with a d v a n c e d Parkinson's disease, in w h o m the clinical benefit b e c o m e s increasingly dependent u p o n delivery of l e v o d o p a to the striatum [Nutt 1987]. Thus attempts to p r o d u c e a m o r e consistent clinical response by the frequent administration of small doses m a y be limited b y cumulative effects on gastric emptying with erratic delivery of subsequent doses to the site of absorption.
Acknowledgements. We are grateful to the British Medical Association for financial support through the Doris Hillier Award, to
Ameer B, Greenblatt DJ, Divoll M, Abernethy DR, Shargel L (1981) High performance liquid chromatographic determination of acetaminophen in plasma: single-dose pharmacokinetic studies. J Chromatogr 226:224-230 Bortolotti M, Frada G, Vezzadini R Bonora G, Barbagallo-Sangiorgi G, Labo G (1987) Influence of gastric acid secretion on interdigestive gastric motor activity and serum motilin in the elderly. Digestion 38:226-233 Evans MA, Broe GA, Triggs E J, Cheung M, Creasey H, Paull PD (1981 a) Gastric emptyingrate and the systemic availability oflevodopa in the elderly Parkinsonian patient. Neurology 31:1288-1294 Evans MA, Triggs EJ, Cheung M, Broe GA, Creasey H (1981b) Gastric emptying rate in the elderly: implications for drug therapy. J Am Geriatr Soc 29:201-205 Fleming JS, Britten AJ, Blake GM, Gray J, Howlett PJ (1987) A general software system for the handling of medical images. Nucl Med Comm 8:270 Gibaldi M, Perrier D (1982) Pharmacokinetics, (2rid edn revised and expanded). Marcel Dekker, New York Horowitz M, Maddern G J, Chatterton BE, Collins PJ, Harding PE, Shearman DJC (1984) Changes in gastric emptying rates with age. Clin Sci 67:213-218 Kupfer RM, HeppelI M, Haggith JW, Bateman DN (1985) Gastric emptying and small-bowel transit rate in the elderly. J Am Geriatr Soc 33:340-343 Kurlan R, Rubin AJ, Miller C, Rivera-Calimlim L, Clarke A, Shoulson I (1986) Duodenal delivery of levodopa for on-offfluctuations in Parkinsonism: Preliminary Observations. Ann Neuro120: 262264 Kurlan R, Rothfleld KP, Woodward WR, Nutt JG, Miller C, Lichter D, Shoulson I (1988) Erratic gastric emptying of levodopa may cause "random" fluctuations of Parkinsonian mobility. Neurology 38:41%421 Moore JG, Tweedy C, Christian PE, Datz FL (1983) Effect of age on gastric emptying of liquid-solid meals in man. Dig Dis Sci 28: 340344 Nutt JG (1987) On-off phenomenon: relation to levodopa pliarmacokinetics and pharmacodynamics. Ann Neuro122:535-540 Quinn N, Parkes JD, Marsden CD (1984) Control of on/off phenomenon by continuous intravenous infusion of ievodopa. Neurology 34:1131-1136 Rashid MV, Bateman DN (1990) Effect of intravenous atropine on gastric emptying, paracetamol absorption, salivary flow and heart rate in young and fit elderly volunteers. Br J Clin Pharmacol 30: 25-34 Robertson DRC, Wood ND, Everest H, Monks K, Waller D G, Renwick AG, George CF (1989) The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmaco128:61-69 Robertson DRC, Renwick AG, Wood ND, Cross N, Macklin BS, Fleming JS, Waller DG, George CF (1990) The influence of levodopa on gastric emptying in man. Br J Clin Pharmaco129:47-53 Sage JI, Schuh L, Heikkila RE, Duvoisin RC (1988) Continuous duodenal infusions of levodopa: plasma concentrations and motor fluctuations in Parkinson's disease. Clin Neuro-Pharmaco111: 3644 Wade DN, Mearrick PT, Birkett D J, Morris J (1974) Variability of 1-dopa absorption in man. Aust NZ J Med 4:138-143 Dr. A. G. Renwick Clinical Pharmacology Group University of Southampton Medical and Biological Sciences Building Bassett Crescent East Southampton SO9 3TU, UK
