The Pharmacokinetics and Effects of Prochlorperazine in Elderly Female Volunteers
Summary The pharmacokinetics and effects of prochlorperazine (PCZ) have been studied in six healthy elderly female volunteers in a double-blind placebo-controlled study of 3.125 mg intravenous (IV) and 25 mg oral PCZ. The pharmacokinetics of IV PCZ in elderly subjects appear similar to those previously obtained in young subjects, with a terminal half-life of 7.5 + 1.8 h after intravenous dosing. Oral bioavailability was low (14.7 ±1.5%). The pharmacological actions of prochlorperazine in elderly people appear to include antidopaminergic (prolactin rise) and anticholinergic (reduced salivary flow) effects. At the dose of PCZ used in this study, no significant haemodynamic or psychomotor changes were observed though there was a trend to prolongation of the movement component of the reaction time.
Introduction Prochlorperazine (PCZ) is a piperazine phenothiazine derivative introduced into medical practice in the mid-1950s. Its main indications include the prevention and symptomatic control of nausea, vomiting, psychiatric and vestibular disorders [1]. Its use in the management of 'dizziness' in elderly patients accounts for the large volume of prescription in this age group. Prescriptions for people aged over 65 years account for over 40% of an annual average of 4 million [2]. Despite its extensive and long use for over three decades, the clinical pharmacology of prochlorperazine has only recently been studied in young healthy volunteers [3, 4]. There are no data on its clinical pharmacology in elderly people. In this study, we have examined the disposition and effects of prochlorperazine in a group of elderly women. We have used an oral (25 mg)
and a low (3.125 mg) intravenous (IV) dose, the latter to reduce the risk of acute extrapyramidal adverse effects (dystonia and akathisia) which were observed in young volunteers [4]. Methods Subjects: Six healthy women aged 69.3 ± 2.3 years, weight 62.2 ± 3.8 kg were studied. All subjects gave written informed consent, and ethical approval was obtained from the local ethics committee. They were assessed by clinical examination, electrocardiography, haematological (full blood count) and biochemical (electrolytes, urea, transaminases, bilirubin, urinalysis) tests. None of the subjects were on routine medication. The volunteers were asked to refrain from alcohol and caffeinated beverages from the evening before, and smoking was not allowed throughout the study period. They were all trained in the various psychomotor tasks used in this experiment on two preliminary days to achieve a steady performance prior to the experiment proper. Procedure: Subjects were studied on three separate Age md Ageing 1992,21:27-31
Downloaded from http://ageing.oxfordjournals.org/ at University of California, San Diego on January 12, 2015
A. O. ISAH, M. D. RAWLINS, D. N. BATEMAN
A. O. ISAH ET AL.
28
0.25, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 h post-dosing for the determination of prochlorperazine and Ndesmethyl prochlorperazine by high-performance liquid chromatography with electrochemical detection (HPLC-EC) [4], the lower limit of the assay is 0.5 ng/ml prochlorperazine and the coefficient of variation 8.3% at 5 ng/ml. Urine was collected for measurement of prochlorperazine and prochlorperazine sulphoxide. Plasma prolactin was determined by a double antibody-binding radio-immunoassay technique (Amersham UK). The pharmacokinetic parameters were derived using standard techniques [7], Data were expressed as mean±SEM. Analysis of variance (two-way) and Friedman's two-way ANOVA were used to determine any significant difference for treatment. Tukey's (HSD) test and Wilcoxon rank sum tests were used for post hoc analysis of significant means. Statistical significance was defined as a p value of less than 0.05.
Results The pharmacokinetic parameters and the mean plasma concentration values after IV and oral dosing are shown in Table I and Figure 1. The plasma concentration following IV dosing declined in a biexponential fashion. The mean apparent volume of distribution (VD) was 14.0 ±1.8 I/kg and total clearance (CIT) was 1.7 + 0.3 1/kg/h. The estimated terminal halflife was 7.5 ± 1.8 h. Following oral administration, prochlorperazine was not detected in two
Table I. Pharmacokinetic parameters in elderly women following intravenous (3.125 mg) and oral (25 mg) prochlorperazine IV 3.125 mg
(years)
Weight (kg)
Tl/2(h) Beta
71 77 74 62 67 65
57.6 80.0 63.8 50.5 54.9 56.4
8.3 8.2
69.3 2.3
62.2
Age
Subject 1 2 3 4 5 6
Mean
±SEM
3.8
15.2 7.4 2.5 3.4 7.5 1.8
Oral 25 mg C
Vd
Cl
d/kg)
(1/kg/h)
(ng/ml)
20.3 16.8 18.9 11.3
1.7 1.4 0.9 1.1 2.6 2.6
1.4
9.3
12.5 14.9 1.8
1.7 0.3
ND* Below lower limit of detection; **Based on four subjects.
1.0 3.6 1.3 ND* ND*
1.8" 0.6
F (%) 11.9 13.8 18.8 14.2 — —
14.7** 1.5
Downloaded from http://ageing.oxfordjournals.org/ at University of California, San Diego on January 12, 2015
occasions at least 7 days apart, and on each occasion received one of the following treatments in random order administered double blind: (a) intravenous (IV) prochlorperazine (PCZ) 3.125 mg with placebo capsules (P); (b) encapsulated prochlorperazine 25 mg with IV normal saline (S); (c) intravenous and oral placebos. Each study session commenced at 08 h 00 after an overnight fast. Twenty minutes before the commencement of measurements, with subjects resting supine, an indwelling cannula was inserted in a convenient vein in the non-dominant forearm under local anaesthesia and kept patent with hepannized saline. Intravenous drug or placebo was administered over a 2-min period into the contralateral antecubital vein. Prochlorperazine or placebo capsules were administered simultaneously and swallowed with 200 ml of water. Drug effects were assessed on each occasion with a battery of tests prior to medication (time 0) and at intervals until 8 h after dosing. These measurements consisted of blood pressure and pulse rate, lying and after standing for 2 minutes. The phase V diastolic pressure was used and the mean of two readings recorded. The mean arterial pressure (MAP) was calculated by adding one third of the pulse pressure to the diastolic pressure. Salivary flow was determined with dental rolls [5]. The psychological tests included critical flicker fusion frequency and choice reaction times assessed with the Leeds Psychomotor tester apparatus [6], together with self-rated restlessness, sedation and dryness of mouth, assessed with an eight-item visual analogue scale [4]. Blood (8 ml) was sampled pre-dose (time 0) and at
PROCHLORPERAZINE IN ELDERLY FEMALE VOLUNTEERS 700
29
r
I
1
2
3
4 5 Tune (hours)
Figure 1. Plasma prochlorperazine concentrations in six healthy elderly women after 3.125 mg IV (A) and 25 mg oral (O) prochlorperazine. subjects. The peak concentration (C mai ) for the remaining four subjects ranged from 1.0 to 3.6 ng/ml and the bioavailability in these four ranged from 11.9 to 18.8%. The TV-desmethyl metabolite was also detected in four subjects, the concentration being 1.47 ± 0.4 ng/ml at 4 h. Urine collection was incomplete for three subjects (one intravenous and two oral sessions). The total amount of drug metabolites excreted in urine was small in relation to the total dose administered (Table II), and proportionally more sulphoxide than parent drug was recovered after oral dosing. The plasma prolactin concentration rose after IV treatment with a peak concentration of 586 ±142 IU/ml at 2 h, declining thereafter (Figure 2). After oral treatment the levels rose from 91 ± 29 /iIU/ml to a peak of 648 ± 72 /ilU/ ml at 6 h, declining thereafter. No significant
F
'^re
P l a s m a P«>lactin concentration in s.x >' y 8 I V (A) a n d 2 5 mg oral (O) prochlorperazine and placebo (D).
health
2 Mean
-
elderl
w o m e n after 3 1 2 : ) m
changes were observed after the placebo treatment. There were no significant changes in the supine and erect pulse rate and blood pressure for any treatment. After IV prochlorperazine, the salivary flow decreased (p < 0.05 at 2h) while no changes were observed after oral prochlorperazine and placebo treatment (Figure 3). 0.21-
PLACEBO
Table II. Total amount of parent drug and sulphoxide excreted in urine over the 8 hour period (mean ±SEM)
Drug/metabolite Prochlorperazine PCZ sulphoxide
(n = 5)
25 mg oral PCZ (/ig) (n = 4)
1.0±0.2 9.6±3.1
1.0 ±0.3 50.0 ±10.2
3.125 mg IV PCZ ( W )
3
4 5 Time(houri)
6
7
8
Figure 3. Salivary flow (mean ± SEM) expressed as difference from placebo values after 3.125 mg IV (A) and 25 mg oral (O) prochlorperazine in six healthy elderly women ( # p
Summary The pharmacokinetics and effects of prochlorperazine (PCZ) have been studied in six healthy elderly female volunteers in a double-blind placebo-controlled study of 3.125 mg intravenous (IV) and 25 mg oral PCZ. The pharmacokinetics of IV PCZ in elderly subjects appear similar to those previously obtained in young subjects, with a terminal half-life of 7.5 + 1.8 h after intravenous dosing. Oral bioavailability was low (14.7 ±1.5%). The pharmacological actions of prochlorperazine in elderly people appear to include antidopaminergic (prolactin rise) and anticholinergic (reduced salivary flow) effects. At the dose of PCZ used in this study, no significant haemodynamic or psychomotor changes were observed though there was a trend to prolongation of the movement component of the reaction time.
Introduction Prochlorperazine (PCZ) is a piperazine phenothiazine derivative introduced into medical practice in the mid-1950s. Its main indications include the prevention and symptomatic control of nausea, vomiting, psychiatric and vestibular disorders [1]. Its use in the management of 'dizziness' in elderly patients accounts for the large volume of prescription in this age group. Prescriptions for people aged over 65 years account for over 40% of an annual average of 4 million [2]. Despite its extensive and long use for over three decades, the clinical pharmacology of prochlorperazine has only recently been studied in young healthy volunteers [3, 4]. There are no data on its clinical pharmacology in elderly people. In this study, we have examined the disposition and effects of prochlorperazine in a group of elderly women. We have used an oral (25 mg)
and a low (3.125 mg) intravenous (IV) dose, the latter to reduce the risk of acute extrapyramidal adverse effects (dystonia and akathisia) which were observed in young volunteers [4]. Methods Subjects: Six healthy women aged 69.3 ± 2.3 years, weight 62.2 ± 3.8 kg were studied. All subjects gave written informed consent, and ethical approval was obtained from the local ethics committee. They were assessed by clinical examination, electrocardiography, haematological (full blood count) and biochemical (electrolytes, urea, transaminases, bilirubin, urinalysis) tests. None of the subjects were on routine medication. The volunteers were asked to refrain from alcohol and caffeinated beverages from the evening before, and smoking was not allowed throughout the study period. They were all trained in the various psychomotor tasks used in this experiment on two preliminary days to achieve a steady performance prior to the experiment proper. Procedure: Subjects were studied on three separate Age md Ageing 1992,21:27-31
Downloaded from http://ageing.oxfordjournals.org/ at University of California, San Diego on January 12, 2015
A. O. ISAH, M. D. RAWLINS, D. N. BATEMAN
A. O. ISAH ET AL.
28
0.25, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 h post-dosing for the determination of prochlorperazine and Ndesmethyl prochlorperazine by high-performance liquid chromatography with electrochemical detection (HPLC-EC) [4], the lower limit of the assay is 0.5 ng/ml prochlorperazine and the coefficient of variation 8.3% at 5 ng/ml. Urine was collected for measurement of prochlorperazine and prochlorperazine sulphoxide. Plasma prolactin was determined by a double antibody-binding radio-immunoassay technique (Amersham UK). The pharmacokinetic parameters were derived using standard techniques [7], Data were expressed as mean±SEM. Analysis of variance (two-way) and Friedman's two-way ANOVA were used to determine any significant difference for treatment. Tukey's (HSD) test and Wilcoxon rank sum tests were used for post hoc analysis of significant means. Statistical significance was defined as a p value of less than 0.05.
Results The pharmacokinetic parameters and the mean plasma concentration values after IV and oral dosing are shown in Table I and Figure 1. The plasma concentration following IV dosing declined in a biexponential fashion. The mean apparent volume of distribution (VD) was 14.0 ±1.8 I/kg and total clearance (CIT) was 1.7 + 0.3 1/kg/h. The estimated terminal halflife was 7.5 ± 1.8 h. Following oral administration, prochlorperazine was not detected in two
Table I. Pharmacokinetic parameters in elderly women following intravenous (3.125 mg) and oral (25 mg) prochlorperazine IV 3.125 mg
(years)
Weight (kg)
Tl/2(h) Beta
71 77 74 62 67 65
57.6 80.0 63.8 50.5 54.9 56.4
8.3 8.2
69.3 2.3
62.2
Age
Subject 1 2 3 4 5 6
Mean
±SEM
3.8
15.2 7.4 2.5 3.4 7.5 1.8
Oral 25 mg C
Vd
Cl
d/kg)
(1/kg/h)
(ng/ml)
20.3 16.8 18.9 11.3
1.7 1.4 0.9 1.1 2.6 2.6
1.4
9.3
12.5 14.9 1.8
1.7 0.3
ND* Below lower limit of detection; **Based on four subjects.
1.0 3.6 1.3 ND* ND*
1.8" 0.6
F (%) 11.9 13.8 18.8 14.2 — —
14.7** 1.5
Downloaded from http://ageing.oxfordjournals.org/ at University of California, San Diego on January 12, 2015
occasions at least 7 days apart, and on each occasion received one of the following treatments in random order administered double blind: (a) intravenous (IV) prochlorperazine (PCZ) 3.125 mg with placebo capsules (P); (b) encapsulated prochlorperazine 25 mg with IV normal saline (S); (c) intravenous and oral placebos. Each study session commenced at 08 h 00 after an overnight fast. Twenty minutes before the commencement of measurements, with subjects resting supine, an indwelling cannula was inserted in a convenient vein in the non-dominant forearm under local anaesthesia and kept patent with hepannized saline. Intravenous drug or placebo was administered over a 2-min period into the contralateral antecubital vein. Prochlorperazine or placebo capsules were administered simultaneously and swallowed with 200 ml of water. Drug effects were assessed on each occasion with a battery of tests prior to medication (time 0) and at intervals until 8 h after dosing. These measurements consisted of blood pressure and pulse rate, lying and after standing for 2 minutes. The phase V diastolic pressure was used and the mean of two readings recorded. The mean arterial pressure (MAP) was calculated by adding one third of the pulse pressure to the diastolic pressure. Salivary flow was determined with dental rolls [5]. The psychological tests included critical flicker fusion frequency and choice reaction times assessed with the Leeds Psychomotor tester apparatus [6], together with self-rated restlessness, sedation and dryness of mouth, assessed with an eight-item visual analogue scale [4]. Blood (8 ml) was sampled pre-dose (time 0) and at
PROCHLORPERAZINE IN ELDERLY FEMALE VOLUNTEERS 700
29
r
I
1
2
3
4 5 Tune (hours)
Figure 1. Plasma prochlorperazine concentrations in six healthy elderly women after 3.125 mg IV (A) and 25 mg oral (O) prochlorperazine. subjects. The peak concentration (C mai ) for the remaining four subjects ranged from 1.0 to 3.6 ng/ml and the bioavailability in these four ranged from 11.9 to 18.8%. The TV-desmethyl metabolite was also detected in four subjects, the concentration being 1.47 ± 0.4 ng/ml at 4 h. Urine collection was incomplete for three subjects (one intravenous and two oral sessions). The total amount of drug metabolites excreted in urine was small in relation to the total dose administered (Table II), and proportionally more sulphoxide than parent drug was recovered after oral dosing. The plasma prolactin concentration rose after IV treatment with a peak concentration of 586 ±142 IU/ml at 2 h, declining thereafter (Figure 2). After oral treatment the levels rose from 91 ± 29 /iIU/ml to a peak of 648 ± 72 /ilU/ ml at 6 h, declining thereafter. No significant
F
'^re
P l a s m a P«>lactin concentration in s.x >' y 8 I V (A) a n d 2 5 mg oral (O) prochlorperazine and placebo (D).
health
2 Mean
-
elderl
w o m e n after 3 1 2 : ) m
changes were observed after the placebo treatment. There were no significant changes in the supine and erect pulse rate and blood pressure for any treatment. After IV prochlorperazine, the salivary flow decreased (p < 0.05 at 2h) while no changes were observed after oral prochlorperazine and placebo treatment (Figure 3). 0.21-
PLACEBO
Table II. Total amount of parent drug and sulphoxide excreted in urine over the 8 hour period (mean ±SEM)
Drug/metabolite Prochlorperazine PCZ sulphoxide
(n = 5)
25 mg oral PCZ (/ig) (n = 4)
1.0±0.2 9.6±3.1
1.0 ±0.3 50.0 ±10.2
3.125 mg IV PCZ ( W )
3
4 5 Time(houri)
6
7
8
Figure 3. Salivary flow (mean ± SEM) expressed as difference from placebo values after 3.125 mg IV (A) and 25 mg oral (O) prochlorperazine in six healthy elderly women ( # p
