Br. J. clin. Pharmac. (1991), 32, 691-695
Gastric emptying in healthy volunteers after multiple doses of levodopa D. G. WALLER, C. ROSEVEARE, A. G. RENWICK, B. MACKLIN & C. F. GEORGE Clinical Pharmacology Group, Centre Block, Southampton General Hospital, Southampton S09 4XY
1 Oral levodopa frequently produces an episodic delay in gastric emptying which leads to multiple peak concentrations of the drug in plasma. We have studied the effects of multiple dosing of levodopa on gastric emptying and levodopa absorption in eight healthy young volunteers in a randomised two-way cross-over study. 2 The plasma concentration-time curves for levodopa were measured after three oral doses of 125 mg given at 2 h intervals and compared with the concentration-time curve for levodopa following administration of two doses of placebo and a single oral dose of 125 mg. 3 A low incidence of multiple peak plasma concentrations of levodopa was detected after all doses of levodopa. The area under the plasma concentration-time curves (AUC) for the final dose of levodopa (150.8 ± 22.0 ,ug ml-' min) was lower than for the two preceding doses (205.7 ± 41.8 and 199.5 ± 51.8,ug ml-l min) but not different from that of the single dose given at the same time of day (141.7 ± 29.1 ,ug ml-l min). This indicates that the lower AUC of the final dose of levodopa was related to the time of administration and not a result of the two preceding doses. 4 The absence of any significant effects of preceding doses of levodopa on gastric emptying was confirmed a) by co-administration of soluble paracetamol, as a marker of gastric emptying, with the second dose of levodopa or placebo and b) by coadministration of radiolabelled DTPA and gamma-camera imaging with the final dose of levodopa on the multiple dosing day and the single dose of levodopa on the placebo
day. 5 This study provides evidence that multiple small doses of levodopa (125 mg) produce no cumulative effects on gastric emptying in healthy young volunteers. However this does not exclude the possibility of cumulative effects in elderly people who have an increased AUC for levodopa after oral administration and a high incidence of multiple peak plasma concentrations of levodopa. Keywords
levodopa
paracetamol
gastric emptying
multiple plasma peaks
Introduction
concentration-time profile of levodopa closely followed each emptying phase. Few pharmacokinetic data have been reported during multiple dosing with levodopa but two studies suggest that peak plasma concentrations of levodopa may be delayed during successive doses when compared to the first dose of the day (Hardie, 1986; Shoulson et al., 1975). It is possible that these results reflect a cumulative effect of levodopa on gastric emptying. Maintenance of steady plasma levodopa concentrations becomes more important with advanced Parkinson's disease and short
Multiple peak plasma concentrations of levodopa are observed frequently after oral dosing (Evans et al., 1981; Robertson et al., 1989; Wade et al., 1974). We have demonstrated that these are the result of an episodic delay in gastric emptying produced by levodopa (Robertson et al., 1990). Following a single oral dose of levodopa (125 mg), taken with the peripheral decarboxylase inhibitor carbidopa, two phases of rapid gastric emptying were detected in the majority of subjects separated by a period of negligible emptying which lasted for an average of 40 min. Peaks in the plasma
Correspondence: Dr D. G. Waller, Clinical Pharmacology Group, Centre Block, Southampton General Hospital, Southampton S09 4XY
691
692
D. G. Waller et al.
dose intervals have been recommended to reduce response fluctuations (Pearce, 1987; Shaw et al., 1979). In these circumstances, delays in gastric emptying could lead to eventual 'dumping' of levodopa accumulated in the stomach. The clinical importance of this potential effect was recently demonstrated by Kurlan etal. (1988). In a detailed study of a single patient with Parkinson's disease they demonstrated that erratic gastric emptying of levodopa contributed to random fluctuations in mobility. The current study compares the plasma drug concentration-time profile of short interval multiple oral doses of levodopa with that after a single dose in healthy young volunteers.
Methods
Eight healthy male volunteers aged 23-25 years and body weight 64.6-82.7 kg were studied. All gave written informed consent and the study was approved by the local ethics committee and the Administration of Radioactive Substances Advisory Committee. Two studies were carried out, separated by at least a week, using a double-blind randomised treatment order. The subjects fasted for 12 h prior to each study. A summary of the protocol is shown in Figure 1. On one day each subject received three oral doses of levodopa 125 mg suspended in 100 ml water, given at 2 h intervals at 09.00 h, 11.00 h and 13.00 h. With the second dose they received 1 g soluble paracetamol in the same 100 ml water as a marker of gastric emptying (Clements et al., 1978), and with the third dose 12 MBq of 99mTc DTPA was given in the same 100 ml of water to monitor gastric emptying. Subjects were imaged under a gamma camera for 2 h after the third dose of levodopa. Carbidopa 100 mg was given orally 1 h before the first dose of levodopa and 50 mg 6 h later, to reduce peripheral decarboxylation of levodopa. Identical meals consisting of two slices of toast with 5 g of margarine, and 100 ml orange juice were given at 10.00 h and 12.00 h. Further food was allowed only when gastric emptying was complete after the third dose of levodopa. Subjects remained semi-recumbent, lying on their backs until 6 h after the first dose of levodopa. Blood (5 ml) was taken for estimation of levodopa at 15 min intervals immediately before and up to 6 h after the first dose of levodopa, and then hourly for a further 6 h. Plasma paracetamol concentrations were also measured between administration of the dose at 11.00 h and the Time(h) -1 0
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Plasma Carbidopa I Levodopa Paracetamol DTPA
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Data analysis Gamma camera images were analysed as previously described (Robertson et al., 1990). A peak in the plasma concentration of levodopa was defined as a rise of at least 10% compared with the previous concentration or between 5 and 10% if it occurred within 15 min of a 10% rise in the plasma paracetamol concentration. The maximum plasma concentrations of levodopa after the second and third doses are given as the absolute concentrations (Cmax) and the increase between the trough and the maximum plasma concentration (C rise). After the single dose of levodopa the area under the concentration-time curve (AUC) was derived by use of the linear trapezoidal rule (Gibaldi & Perrier, 1982) with extrapolation to infinity by the addition of the last measurable concentration divided by the elimination rate constant. The AUC values for the three doses of levodopa on the multiple dosing day were extrapolated to infinity using the terminal elimination rate constant after the final dose (Xz) and corrected for any carry over from preceding doses. Values of X, were based on loglinear regression analysis applied to the last 6-9 plasma concentrations, which gave r values of 0.98 or more. Thus the AUC for the first dose was calculated by the linear trapezoidal rule from 09.00 h until 11.00 h and extrapolated to infinity by the addition of the concentration at 11.00 h divided by Xz (C11.00/Az). The AUC of the second dose was calculated by the trapezoidal rule between 11.00 h and 13.00 h with extrapolation to infinity by the addition of the concentration at 13.00 h divided by Xz (C13.00/AZ) minus C11.00/AX. The AUC for the final dose was calculated by the trapezoidal rule from 13.00 h to the last measurable concentration (Clast) and extrapolated to infinity by the addition of Clast/Xz and corrected by the subtraction of C13.00/Xz. Results are expressed as mean ± s.d. Statistical analyses were by Wilcoxon signed rank test and two-way analysis of variance.
6 7 8 9101112 111 1
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t t t t t I
*
end of sampling at 21.00 h. Plasma samples were stored at -20° C until analysis for levodopa (Robertson et al., 1989) and paracetamol (Ameer et al., 1981) by high performance liquid chromatography. On the second study day the protocol was identical, except that levodopa was omitted from the 100 ml water or paracetamol solution given at 09.00 h and 11.00 h and the only dose of levodopa was given 13.00 h to coincide with the timing of the third dose on the other study day.
Results
Effects on gastric emptying
I I
Active day only Figure 1 Summary of experimental protocol.
Paracetamol data (Figure 2) The values of Cmax and tmax of paracetamol (Table 1) given at 11.00 h were similar on the 2 study days. Only two of the paracetamol concentration-time curves showed secondary peaks between 11.00 h and 13.00 h. These occurred in one subject 1 h after dosing with levodopa and in a different
693
Levodopa and gastric emptying 24
study days indicated that the first two doses of levodopa during multiple dosing had no effect on measures of gastric emptying after the third dose (Table 2).
.20-
CD 16-
E 12
CouCu cu
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Time6 (h)7 8 9 10 11 12 Figure 2 Plasma concentration-time curves for paracetamol following a single dose of paracetamol given with the second of three doses of levodopa (circles) or 2 h prior to a single dose of levodopa (triangles). The results are the means of eight subjects with s.e. mean errors indicated by the vertical bars. 00
1
2
3
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5
Table 1 Pharmacokinetics of paracetamol given alone or in combination with levodopa
Cmax (,ug ml-') tmax (min)
AUC(pugml min)
Control day' 15.9 ± 4.2
Multiple dosing da/ 19.2 ± 8.6
19 ± 7 2200 ± 507 1
2793 ± 1141* 1
19 ± 11
Multiple peaks (n) The results are mean ± s.d. for eight subjects. * P < 0.005 by signed rank test. 1 Paracetamol given at 11.00 h without levodopa. 2 Paracetamol given at 11.00 h with levodopa and following levodopa at 09.00 h.
Levodopa data After almost all doses of levodopa, the observed maximum concentration of levodopa (Cmax) occurred in the sample taken 15 min after dosing (Figure 3). Thus the time to maximum concentration (tmax) showed no evidence of delay during multiple dosing (Table 3). Multiple peak plasma concentrations of levodopa were found after only seven of the 32 doses within the first 2 h after each dose (Table 3). The subject with delayed gastric emptying on the single dose control day (see gamma camera data above) showed an initial peak plasma concentration of levodopa at 15 min but a subsequent large increase (from 147 ng ml-1 to 617 ng ml-1) between 105 and 180 min. The greatest increases detected for secondary peaks on the multiple dose day were 33% at 75 min after one of the 09.00 h doses and 28% at 60 min in a different subject after the 11.00 h dose, the latter being accompanied by a 29% increase in plasma paracetamol concentration. The other secondary increases were between 10 and 15% only (at 105 min after a 09.00 h dose; at 90 min after an 11.00 h dose; at 60 and 90 min after two 13.00 h doses); of these, the 12% increase at 60 min after the 13.00 h dose coincided with the end of a plateau on the gamma camera scan. The other three small increases did not coincide with either a secondary peak of paracetamol or the end of a plateau on the gamma camera scan. 4.0 3.5 _
subject 2 h after dosing on the control day. The AUC for paracetamol was significantly higher when given with levodopa and there was a much greater variability.
Gamma camera data On both study days most subjects showed mono-exponential or simple biphasic patterns of gastric emptying of 99mTc-DTPA given with the 13.00 h dose of levodopa. In one subject 48% of the dose of 99mTc DTPA remained in the gastric region of interest at the end of 2 h after the single dose of levodopa. On the multiple dosing day in that subject, and on both days in all other subjects, over 80% of the radiolabel had left the region of interest within 2 h. The incidence of plateaux in the gamma scans was low on both study days despite the co-administration of levodopa with 99mTc DTPA on each occasion. Comparison between the two
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Figure 3 Plasma concentration-time curves for levodopa after single (triangles) and multiple (circles) doses of levodopa in healthy volunteers. The results are the means of eight subjects with s.e. mean indicated by the vertical bars.
Table 2 Gastric emptying assessed by gamima camera data Control day' Multiple dosing day 13 ± 6 29 ± 30 Time to 50% emptying (min) 40 ± 22 38 ± 177 Time to 80% emptying (min) 24 ± 10 50 ± 71 Mean transit time (min) 11 ± 6 15 ± 8 Initial emptying half-life (min) 1 1 Number of subjects showing a plateau phase The results are the mean ± s.d. for eight subjects except where given as a superscript. 1 Dose of 99mTc DTPA given at 13.00 h with a single dose of levodopa. 2 Dose of 99mTc DTPA given at 13.00 h with levodopa following two doses of levodopa (09.00 h and 11.00 h).
694
D. G. Waller et al. Table 3 Plasma pharmacokinetics of levodopa
Cmax (,wg ml 1) tmax (min) C rise (,ug ml- 1) AUC (pgml -min)1: Multiple peaks (n)
Multiple dosing day 11.00 h
Control day 13.00 h
09.00 h
1.45 ± 0.39 23 ± 8
2.84 ± 1.03 21 ± 8
-
141.7 ± 29.1 1
-
205.7 ± 41.8 2
3.27 ± 1.17 15 ± 0 2.84 ± 1.08 199.5 ± 51.8 2
13.00 h 2.84 ± 0.71 19 ± 7 2.18 ± 0.73 150.8 ± 22.0 2
t Extrapolated to infinity and corrected for carry over from preceding doses.
The AUCs for each dose of levodopa (corrected for previous and subsequent doses), were similar for the first two doses on the multiple-dose day. The mean rise in concentration for the second dose was identical to the initial rise for the first dose. However, there was a smaller rise for the third dose, which produced a significantly lower AUC than either of the preceding doses (P < 0.05). However, the AUC of this third dose at 13.00 h (151 + 22 ,ug ml-' min) was not significantly different from that of the single dose given at 13.00 h on the control day (142 ± 29 ,ug ml-' min).
Discussion
The results of this study do not support the initial hypothesis that the effects of levodopa on gastric emptying could be exaggerated by preceding doses of levodopa. However, the lack of plateaux on the gamma camera scans and the small number of secondary peaks in the plasma levodopa concentration-time curve contrast with our previous findings after single doses (Robertson et al., 1989, 1990, 1991). Only one subject in the current study provided clear evidence of a plateau, which was observed on both study days and was longer after the single dose of levodopa. These scans were associated with secondary peaks in the plasma levodopa concentration. The majority of second peak plasma concentrations of levodopa detected in earlier studies occurred between 60 and 75 min after oral dosing (Robertson et al., 1989, 1990, 1991). In the current study the first (09.00 h) dose of levodopa was given under identical conditions to previous studies except that subjects were fed after 1 h. It is possible that inhibition of gastric emptying by the light meal may have prolonged a period of inhibition of gastric emptying due to levodopa so that emptying resumed after the second dose had been taken. No gastric emptying data were obtained to explore this possibility. However, the consistently rapid absorption of the second dose of levodopa and the similar AUC data for the first two doses do not support this suggestion. In addition, we have shown previously that secondary peak concentrations of levodopa are common when the dose is given 1 h after a low protein meal (10.5 g protein) (Robertson et al., 1991) which indicates that a light meal would be unlikely to alter the effect of levodopa on gastric emptying. Multiple peak plasma concentrations of paracetamol were detected once after the second dose of levodopa
(accompanied by a rise in levodopa concentration) and once on the control day. Secondary peaks in paracetamol concentration are unusual when the compound is given alone (Clements et al., 1978; Robertson et al., 1990). Their occasional occurrence may be due to the timing of the dose relative to the natural phasic gastric motor activity (Oberle & Amidon, 1987), and could have been influenced by the food taken 1 h prior to these doses. There are few published observations of the pharmacokinetics of levodopa during multiple dosing. Two studies involving Parkinsonian patients found that levodopa doses given later in the day occasionally failed to increase plasma levodopa concentrations (Hardie et al., 1986; Nutt et al., 1977). Nutt et al. (1977) suggested that these findings could be explained by the ingestion of a meal taken 2 h before doses. Shoulson et al. (1975) reported that the maximum plasma levodopa concentration was 50% lower after the second and third doses compared with the first dose of the day. The timing and nature of any meals taken by the subjects was not reported for that study. Two of these studies (Hardie et al., 1986; Shoulson et al., 1975) also report a delay to peak plasma levodopa concentration when later doses were compared with the initial dose, which contrasts with the current observations in young volunteers. In this study, the AUC of levodopa was similar after the third dose to that of the single dose given at 13.00 h on the other study day. However, there was a significant reduction in the AUC of the third dose (13.00 h) when compared with the first two (09.00 h and 11.00 h). There are several potential explanations for this observation; e.g. a circadian variation in absorption, first-pass metabolism or clearance cannot be excluded. Volunteers received a low protein meal prior to the third dose, which has been shown to reduce the AUC for levodopa (Baruzzi et al., 1987; Robertson et al., 1991). A further contributory mechanism may be the timing of the doses of decarboxylase inhibitor. The effect of the dose of carbidopa given at 08.00 h may have declined by the time the third dose of levodopa was given, which would enhance first-pass metabolism of the later doses of levodopa in either the stomach, gut wall or liver, and thereby lower the AUC. The dose of levodopa chosen for the current study has produced a variable incidence of twin plasma peaks in previous studies of young volunteers. After single dosing with 125 mg, given with carbidopa, double peaks were found in four of eight (Robertson et al., 1989) and six of eight subjects (Robertson et al., 1990). We conclude from our results that there was no
Levodopa and gastric emptying evidence that sequential dosing with 125 mg levodopa at 2 h intervals has cumulative effects on gastric emptying or produces any alteration in levodopa pharmacokinetics in young volunteers. However, the possibility remains that
695
elderly subjects, who show an increased AUC for levodopa and a greater incidence of double plasma levodopa peaks after this dose (Robertson et al., 1989), may be more susceptible.
References Ameer, B., Greenblatt, D. J., Divoll, M., Abernethy, D. R. & Shargel, L. (1981). High performance liquid chromatographic determination of acetaminophen in plasma: single dose pharmacokinetic studies. J. Chromatogr., 226, 224230. Baruzzi, A., Contin, M., Riva, R., Procaccianti, G., Albani, F., Tonello, C., Zoni, E. & Martinelli, P. (1987). The influence of meal ingestion time on the pharmacokinetics of orally administered levodopa in Parkinsonian patients. Clin. Neuropharmac., 10, 527-537. Clements, J. A., Heading, R. C., Nimmo, W. S. & Prescott, L. F. (1978). Kinetics of acetaminophen absorption and gastric emptying in man. Clin. Pharmac. Ther., 24, 420431. Evans, M. A., Broe, G. A., Triggs, E. J., Cheung, M., Creasey, H. & Paull, P. D. (1981). Gastric emptying rate and the systemic availability of levodopa in the elderly Parkinsonian patient. Neurology, 31, 1288-1294. Gibaldi, M. & Perrier, D. (1982). In Pharmacokinetics, second edition. New York: Marcel Dekker. Hardie, R. (1986). The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson's disease who exhibit on-off fluctuations. Br. J. clin Pharmac., 22, 429436. Kurlan, R., Rothfield, K. P., Woodward, W. R., Nutt, J. G., Miller, C., Lichter, D. & Shoulson, I. (1988). Erratic gastric emptying of levodopa may cause "random" fluctuations of Parkinsonian mobility. Neurology, 38, 419-421. Nutt, J. G., Woodward, W. R., Hammerstad, J. P., Carter, J. H. & Anderson, J. L. (1984). The on-off phenomenon in Parkinson's disease-relation to levodopa absorption and transport. New Engl. J. Med., 310, 483-488. Oberle, R. L. & Amidon, G. L. (1987). The influence of
variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon. J. Pharmacokin. Biopharm., 15, 529-544. Pearce, J. (1987). Modern treatment of Parkinson's Disease. Br. J. hosp. Med., 37, 59-66. Robertson, D. R. C., Wood, N. D., Everest, H., Monks, K., Waller, D. G., Renwick, A. G. & George, C. F. (1989). The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br. J. clin. Pharmac., 28, 61-69. Robertson, D. R. C., Renwick, A. G., Wood, N. D., Cross, N., Macklin, B. S., Fleming, J. S., Waller, D. G. & George, C. F. (1990). The influence of levodopa on gastric emptying in man. Br. J. clin. Pharmac., 29, 47-53. Robertson, D. R. C., Higginson, I., Macklin, B. S., Renwick, A. G., Waller, D. G. & George, C. F. (1991). The influence of protein-containing meals on the pharmacokinetics of levodopa in healthy volunteers. Br. J. clin. Pharmac., 31, 413-417. Shaw, K. M., Lees, A. J. & Stern, G. M. (1979). The impact of treatment with L-dopa on Parkinsonism. Quart. J. Med., 49, 283-293. Shoulson, I., Glanbiger, G. A. & Chase, T. N. (1975). On-off response: clinical and biochemical correlations during oral and intravenous levodopa administration in Parkinsonian patients. Neurology, 25, 1144-1148. Wade, D. N., Mearrick, P. T., Birkett, D. J. & Morris, J. (1974). Variability of 1-dopa absorption in man. Aust. N. Z. J. Med., 4, 138-143.
(Received 15 May 1991, accepted 16 July 1991)
Gastric emptying in healthy volunteers after multiple doses of levodopa D. G. WALLER, C. ROSEVEARE, A. G. RENWICK, B. MACKLIN & C. F. GEORGE Clinical Pharmacology Group, Centre Block, Southampton General Hospital, Southampton S09 4XY
1 Oral levodopa frequently produces an episodic delay in gastric emptying which leads to multiple peak concentrations of the drug in plasma. We have studied the effects of multiple dosing of levodopa on gastric emptying and levodopa absorption in eight healthy young volunteers in a randomised two-way cross-over study. 2 The plasma concentration-time curves for levodopa were measured after three oral doses of 125 mg given at 2 h intervals and compared with the concentration-time curve for levodopa following administration of two doses of placebo and a single oral dose of 125 mg. 3 A low incidence of multiple peak plasma concentrations of levodopa was detected after all doses of levodopa. The area under the plasma concentration-time curves (AUC) for the final dose of levodopa (150.8 ± 22.0 ,ug ml-' min) was lower than for the two preceding doses (205.7 ± 41.8 and 199.5 ± 51.8,ug ml-l min) but not different from that of the single dose given at the same time of day (141.7 ± 29.1 ,ug ml-l min). This indicates that the lower AUC of the final dose of levodopa was related to the time of administration and not a result of the two preceding doses. 4 The absence of any significant effects of preceding doses of levodopa on gastric emptying was confirmed a) by co-administration of soluble paracetamol, as a marker of gastric emptying, with the second dose of levodopa or placebo and b) by coadministration of radiolabelled DTPA and gamma-camera imaging with the final dose of levodopa on the multiple dosing day and the single dose of levodopa on the placebo
day. 5 This study provides evidence that multiple small doses of levodopa (125 mg) produce no cumulative effects on gastric emptying in healthy young volunteers. However this does not exclude the possibility of cumulative effects in elderly people who have an increased AUC for levodopa after oral administration and a high incidence of multiple peak plasma concentrations of levodopa. Keywords
levodopa
paracetamol
gastric emptying
multiple plasma peaks
Introduction
concentration-time profile of levodopa closely followed each emptying phase. Few pharmacokinetic data have been reported during multiple dosing with levodopa but two studies suggest that peak plasma concentrations of levodopa may be delayed during successive doses when compared to the first dose of the day (Hardie, 1986; Shoulson et al., 1975). It is possible that these results reflect a cumulative effect of levodopa on gastric emptying. Maintenance of steady plasma levodopa concentrations becomes more important with advanced Parkinson's disease and short
Multiple peak plasma concentrations of levodopa are observed frequently after oral dosing (Evans et al., 1981; Robertson et al., 1989; Wade et al., 1974). We have demonstrated that these are the result of an episodic delay in gastric emptying produced by levodopa (Robertson et al., 1990). Following a single oral dose of levodopa (125 mg), taken with the peripheral decarboxylase inhibitor carbidopa, two phases of rapid gastric emptying were detected in the majority of subjects separated by a period of negligible emptying which lasted for an average of 40 min. Peaks in the plasma
Correspondence: Dr D. G. Waller, Clinical Pharmacology Group, Centre Block, Southampton General Hospital, Southampton S09 4XY
691
692
D. G. Waller et al.
dose intervals have been recommended to reduce response fluctuations (Pearce, 1987; Shaw et al., 1979). In these circumstances, delays in gastric emptying could lead to eventual 'dumping' of levodopa accumulated in the stomach. The clinical importance of this potential effect was recently demonstrated by Kurlan etal. (1988). In a detailed study of a single patient with Parkinson's disease they demonstrated that erratic gastric emptying of levodopa contributed to random fluctuations in mobility. The current study compares the plasma drug concentration-time profile of short interval multiple oral doses of levodopa with that after a single dose in healthy young volunteers.
Methods
Eight healthy male volunteers aged 23-25 years and body weight 64.6-82.7 kg were studied. All gave written informed consent and the study was approved by the local ethics committee and the Administration of Radioactive Substances Advisory Committee. Two studies were carried out, separated by at least a week, using a double-blind randomised treatment order. The subjects fasted for 12 h prior to each study. A summary of the protocol is shown in Figure 1. On one day each subject received three oral doses of levodopa 125 mg suspended in 100 ml water, given at 2 h intervals at 09.00 h, 11.00 h and 13.00 h. With the second dose they received 1 g soluble paracetamol in the same 100 ml water as a marker of gastric emptying (Clements et al., 1978), and with the third dose 12 MBq of 99mTc DTPA was given in the same 100 ml of water to monitor gastric emptying. Subjects were imaged under a gamma camera for 2 h after the third dose of levodopa. Carbidopa 100 mg was given orally 1 h before the first dose of levodopa and 50 mg 6 h later, to reduce peripheral decarboxylation of levodopa. Identical meals consisting of two slices of toast with 5 g of margarine, and 100 ml orange juice were given at 10.00 h and 12.00 h. Further food was allowed only when gastric emptying was complete after the third dose of levodopa. Subjects remained semi-recumbent, lying on their backs until 6 h after the first dose of levodopa. Blood (5 ml) was taken for estimation of levodopa at 15 min intervals immediately before and up to 6 h after the first dose of levodopa, and then hourly for a further 6 h. Plasma paracetamol concentrations were also measured between administration of the dose at 11.00 h and the Time(h) -1 0
I
Plasma Carbidopa I Levodopa Paracetamol DTPA
11
1
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3
4
1 1 iiil1 i ii 1
5 1
tIttttttttttttlttlttttttt t
I
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I
Data analysis Gamma camera images were analysed as previously described (Robertson et al., 1990). A peak in the plasma concentration of levodopa was defined as a rise of at least 10% compared with the previous concentration or between 5 and 10% if it occurred within 15 min of a 10% rise in the plasma paracetamol concentration. The maximum plasma concentrations of levodopa after the second and third doses are given as the absolute concentrations (Cmax) and the increase between the trough and the maximum plasma concentration (C rise). After the single dose of levodopa the area under the concentration-time curve (AUC) was derived by use of the linear trapezoidal rule (Gibaldi & Perrier, 1982) with extrapolation to infinity by the addition of the last measurable concentration divided by the elimination rate constant. The AUC values for the three doses of levodopa on the multiple dosing day were extrapolated to infinity using the terminal elimination rate constant after the final dose (Xz) and corrected for any carry over from preceding doses. Values of X, were based on loglinear regression analysis applied to the last 6-9 plasma concentrations, which gave r values of 0.98 or more. Thus the AUC for the first dose was calculated by the linear trapezoidal rule from 09.00 h until 11.00 h and extrapolated to infinity by the addition of the concentration at 11.00 h divided by Xz (C11.00/Az). The AUC of the second dose was calculated by the trapezoidal rule between 11.00 h and 13.00 h with extrapolation to infinity by the addition of the concentration at 13.00 h divided by Xz (C13.00/AZ) minus C11.00/AX. The AUC for the final dose was calculated by the trapezoidal rule from 13.00 h to the last measurable concentration (Clast) and extrapolated to infinity by the addition of Clast/Xz and corrected by the subtraction of C13.00/Xz. Results are expressed as mean ± s.d. Statistical analyses were by Wilcoxon signed rank test and two-way analysis of variance.
6 7 8 9101112 111 1
l1
t t t t t I
*
end of sampling at 21.00 h. Plasma samples were stored at -20° C until analysis for levodopa (Robertson et al., 1989) and paracetamol (Ameer et al., 1981) by high performance liquid chromatography. On the second study day the protocol was identical, except that levodopa was omitted from the 100 ml water or paracetamol solution given at 09.00 h and 11.00 h and the only dose of levodopa was given 13.00 h to coincide with the timing of the third dose on the other study day.
Results
Effects on gastric emptying
I I
Active day only Figure 1 Summary of experimental protocol.
Paracetamol data (Figure 2) The values of Cmax and tmax of paracetamol (Table 1) given at 11.00 h were similar on the 2 study days. Only two of the paracetamol concentration-time curves showed secondary peaks between 11.00 h and 13.00 h. These occurred in one subject 1 h after dosing with levodopa and in a different
693
Levodopa and gastric emptying 24
study days indicated that the first two doses of levodopa during multiple dosing had no effect on measures of gastric emptying after the third dose (Table 2).
.20-
CD 16-
E 12
CouCu cu
E
Cu4
Time6 (h)7 8 9 10 11 12 Figure 2 Plasma concentration-time curves for paracetamol following a single dose of paracetamol given with the second of three doses of levodopa (circles) or 2 h prior to a single dose of levodopa (triangles). The results are the means of eight subjects with s.e. mean errors indicated by the vertical bars. 00
1
2
3
4
5
Table 1 Pharmacokinetics of paracetamol given alone or in combination with levodopa
Cmax (,ug ml-') tmax (min)
AUC(pugml min)
Control day' 15.9 ± 4.2
Multiple dosing da/ 19.2 ± 8.6
19 ± 7 2200 ± 507 1
2793 ± 1141* 1
19 ± 11
Multiple peaks (n) The results are mean ± s.d. for eight subjects. * P < 0.005 by signed rank test. 1 Paracetamol given at 11.00 h without levodopa. 2 Paracetamol given at 11.00 h with levodopa and following levodopa at 09.00 h.
Levodopa data After almost all doses of levodopa, the observed maximum concentration of levodopa (Cmax) occurred in the sample taken 15 min after dosing (Figure 3). Thus the time to maximum concentration (tmax) showed no evidence of delay during multiple dosing (Table 3). Multiple peak plasma concentrations of levodopa were found after only seven of the 32 doses within the first 2 h after each dose (Table 3). The subject with delayed gastric emptying on the single dose control day (see gamma camera data above) showed an initial peak plasma concentration of levodopa at 15 min but a subsequent large increase (from 147 ng ml-1 to 617 ng ml-1) between 105 and 180 min. The greatest increases detected for secondary peaks on the multiple dose day were 33% at 75 min after one of the 09.00 h doses and 28% at 60 min in a different subject after the 11.00 h dose, the latter being accompanied by a 29% increase in plasma paracetamol concentration. The other secondary increases were between 10 and 15% only (at 105 min after a 09.00 h dose; at 90 min after an 11.00 h dose; at 60 and 90 min after two 13.00 h doses); of these, the 12% increase at 60 min after the 13.00 h dose coincided with the end of a plateau on the gamma camera scan. The other three small increases did not coincide with either a secondary peak of paracetamol or the end of a plateau on the gamma camera scan. 4.0 3.5 _
subject 2 h after dosing on the control day. The AUC for paracetamol was significantly higher when given with levodopa and there was a much greater variability.
Gamma camera data On both study days most subjects showed mono-exponential or simple biphasic patterns of gastric emptying of 99mTc-DTPA given with the 13.00 h dose of levodopa. In one subject 48% of the dose of 99mTc DTPA remained in the gastric region of interest at the end of 2 h after the single dose of levodopa. On the multiple dosing day in that subject, and on both days in all other subjects, over 80% of the radiolabel had left the region of interest within 2 h. The incidence of plateaux in the gamma scans was low on both study days despite the co-administration of levodopa with 99mTc DTPA on each occasion. Comparison between the two
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Figure 3 Plasma concentration-time curves for levodopa after single (triangles) and multiple (circles) doses of levodopa in healthy volunteers. The results are the means of eight subjects with s.e. mean indicated by the vertical bars.
Table 2 Gastric emptying assessed by gamima camera data Control day' Multiple dosing day 13 ± 6 29 ± 30 Time to 50% emptying (min) 40 ± 22 38 ± 177 Time to 80% emptying (min) 24 ± 10 50 ± 71 Mean transit time (min) 11 ± 6 15 ± 8 Initial emptying half-life (min) 1 1 Number of subjects showing a plateau phase The results are the mean ± s.d. for eight subjects except where given as a superscript. 1 Dose of 99mTc DTPA given at 13.00 h with a single dose of levodopa. 2 Dose of 99mTc DTPA given at 13.00 h with levodopa following two doses of levodopa (09.00 h and 11.00 h).
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D. G. Waller et al. Table 3 Plasma pharmacokinetics of levodopa
Cmax (,wg ml 1) tmax (min) C rise (,ug ml- 1) AUC (pgml -min)1: Multiple peaks (n)
Multiple dosing day 11.00 h
Control day 13.00 h
09.00 h
1.45 ± 0.39 23 ± 8
2.84 ± 1.03 21 ± 8
-
141.7 ± 29.1 1
-
205.7 ± 41.8 2
3.27 ± 1.17 15 ± 0 2.84 ± 1.08 199.5 ± 51.8 2
13.00 h 2.84 ± 0.71 19 ± 7 2.18 ± 0.73 150.8 ± 22.0 2
t Extrapolated to infinity and corrected for carry over from preceding doses.
The AUCs for each dose of levodopa (corrected for previous and subsequent doses), were similar for the first two doses on the multiple-dose day. The mean rise in concentration for the second dose was identical to the initial rise for the first dose. However, there was a smaller rise for the third dose, which produced a significantly lower AUC than either of the preceding doses (P < 0.05). However, the AUC of this third dose at 13.00 h (151 + 22 ,ug ml-' min) was not significantly different from that of the single dose given at 13.00 h on the control day (142 ± 29 ,ug ml-' min).
Discussion
The results of this study do not support the initial hypothesis that the effects of levodopa on gastric emptying could be exaggerated by preceding doses of levodopa. However, the lack of plateaux on the gamma camera scans and the small number of secondary peaks in the plasma levodopa concentration-time curve contrast with our previous findings after single doses (Robertson et al., 1989, 1990, 1991). Only one subject in the current study provided clear evidence of a plateau, which was observed on both study days and was longer after the single dose of levodopa. These scans were associated with secondary peaks in the plasma levodopa concentration. The majority of second peak plasma concentrations of levodopa detected in earlier studies occurred between 60 and 75 min after oral dosing (Robertson et al., 1989, 1990, 1991). In the current study the first (09.00 h) dose of levodopa was given under identical conditions to previous studies except that subjects were fed after 1 h. It is possible that inhibition of gastric emptying by the light meal may have prolonged a period of inhibition of gastric emptying due to levodopa so that emptying resumed after the second dose had been taken. No gastric emptying data were obtained to explore this possibility. However, the consistently rapid absorption of the second dose of levodopa and the similar AUC data for the first two doses do not support this suggestion. In addition, we have shown previously that secondary peak concentrations of levodopa are common when the dose is given 1 h after a low protein meal (10.5 g protein) (Robertson et al., 1991) which indicates that a light meal would be unlikely to alter the effect of levodopa on gastric emptying. Multiple peak plasma concentrations of paracetamol were detected once after the second dose of levodopa
(accompanied by a rise in levodopa concentration) and once on the control day. Secondary peaks in paracetamol concentration are unusual when the compound is given alone (Clements et al., 1978; Robertson et al., 1990). Their occasional occurrence may be due to the timing of the dose relative to the natural phasic gastric motor activity (Oberle & Amidon, 1987), and could have been influenced by the food taken 1 h prior to these doses. There are few published observations of the pharmacokinetics of levodopa during multiple dosing. Two studies involving Parkinsonian patients found that levodopa doses given later in the day occasionally failed to increase plasma levodopa concentrations (Hardie et al., 1986; Nutt et al., 1977). Nutt et al. (1977) suggested that these findings could be explained by the ingestion of a meal taken 2 h before doses. Shoulson et al. (1975) reported that the maximum plasma levodopa concentration was 50% lower after the second and third doses compared with the first dose of the day. The timing and nature of any meals taken by the subjects was not reported for that study. Two of these studies (Hardie et al., 1986; Shoulson et al., 1975) also report a delay to peak plasma levodopa concentration when later doses were compared with the initial dose, which contrasts with the current observations in young volunteers. In this study, the AUC of levodopa was similar after the third dose to that of the single dose given at 13.00 h on the other study day. However, there was a significant reduction in the AUC of the third dose (13.00 h) when compared with the first two (09.00 h and 11.00 h). There are several potential explanations for this observation; e.g. a circadian variation in absorption, first-pass metabolism or clearance cannot be excluded. Volunteers received a low protein meal prior to the third dose, which has been shown to reduce the AUC for levodopa (Baruzzi et al., 1987; Robertson et al., 1991). A further contributory mechanism may be the timing of the doses of decarboxylase inhibitor. The effect of the dose of carbidopa given at 08.00 h may have declined by the time the third dose of levodopa was given, which would enhance first-pass metabolism of the later doses of levodopa in either the stomach, gut wall or liver, and thereby lower the AUC. The dose of levodopa chosen for the current study has produced a variable incidence of twin plasma peaks in previous studies of young volunteers. After single dosing with 125 mg, given with carbidopa, double peaks were found in four of eight (Robertson et al., 1989) and six of eight subjects (Robertson et al., 1990). We conclude from our results that there was no
Levodopa and gastric emptying evidence that sequential dosing with 125 mg levodopa at 2 h intervals has cumulative effects on gastric emptying or produces any alteration in levodopa pharmacokinetics in young volunteers. However, the possibility remains that
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elderly subjects, who show an increased AUC for levodopa and a greater incidence of double plasma levodopa peaks after this dose (Robertson et al., 1989), may be more susceptible.
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(Received 15 May 1991, accepted 16 July 1991)
