European Journal of Clinical Pharmacology
Europ. J. clin. Pharmacol. 11,141-147 (1977)
© by Springer Verlag 1977
Plasma Levels and Half Lives of Thioridazine and Some of Its Metabolites II. Low Doses in Older Psychiatric Patients R. G. Muusze 1 and F. A. J. Vanderheeren 2 1Psychiatric Clinic Delft, Netherlands, and 2 Department of Psychiatry, University of Ghent, Ghent, Belgium
Summary. Plasma-levels of thioridazine, mesoridazine, sulphoridazine and two other metabolites were determined in ten older chronic psychotic patients on thioridazine therapy. The plasma-level before the morning dose of thioridazine was the most reliable parameter for clinical studies. An intra-individual relationship between lower doses of thioridazine and plasma-levels was found. The percentage contribution of psychoactive compounds to the total sum of "thioridazine plus metabolites" ranged from 43-74%. The mean "early disappearance half-life" of thioridazine was 5 hours, and its mean "late disappearance half-life" was 26 hours.
Table la. Clinical details and treatment of patients in the drugwithdrawal group Patient Age
years kg
Daily dose (mg) thioridazine
DF
56
76
thioridazine
2 × 75
AP
68
59
thioridazine cyproheptadine orphenadrine vitamin C vitamincombination a
2 × 100
thioridazine
2 × 25
thioridazine distigminebromide
2 x 50
thioridazine phenobarbitone
2 × 75
FD
Key words: Phenothiazine, thioridazine, plasma level, metabolic pattern, half life, man, schizophrenia.
Weight Drug
GS
PL
57 73
74
72 85
54
other drugs
2x4 2x50 3x50
3x5 3 x75
Mean daily dose of thioridazine 130 mg
In this investigation, certain pharmacological and pharmacokinetic parameters of thioridazine and four metabolites were determined in a population of ten older chronically psychotic patients, who received a low long term maintenance therapy with thioridazine (50-200 rag/day). The influence of the time of blood sampling on the plasma level, the reliability and pharmacological meaning of plasma levels and the relationship between dose and plasma level are all parameters of importance, and they should be known before the relationship between plasma level and clinical effect of a drug is studied.
Vitamin combination: Davitamon 10 (one daily) contains: retinol palmitate 1000 IU, thiamine mononitrate 0,5 rag, riboflavine 0,5 rag, nicotinamide 5 mg, pyridoxine chloride 0,2 mg, cyanocobalamine 0,5 mcg, calcium pantothenate 1 mg, ascorbic acid 20 mg, ergocalciferol 400 IU, tocoferol-alpha-acetate 1 mg). The same patient also received hydroxocobalamine 1000 mcg monthly. DF: AP: FD: GS: PL:
formerly pulmonary tuberculosis, now emphysema, normal blood values vitamin B12 deficiency, normal blood values diabetes mellitus, treated with diet; normal blood values right bundle branch block on electrocardiogram, normal blood values formerly pulmonary tuberculosis, at present diabetes mellitus, treated with diet; blood: red cell count 3 770 000 per mm 3, gamma GT 34 U/l, cholesterol 7.9 mmol/1
142
R.G. Muusze and F. A. J. Vanderheeren: Thioridazine Plasma Levels II
Table lb. Clinical details and treatment of patients in the drngmaintained group Patient Age
Weight Drug
thioridazine other drugs
years kg HeD PH HuD LL
WP
49 66 54 70
71 67 75 78
79
62
Daily dose (mg)
thioridazine thioridazine thioridazine thioridazine phenytoin phenobarbitone cyclandelate thioridazine
2 × 75 2 × 75 2 × 75 2 × 50 3 × 50 3 × 50 1 x 200 2 × 50
mean daily dose of thioridazine 130 mg Patients HeD, PH, HuD and WP: healthy, normal blood values. Patient LL: mild chronic bronchitis, slightly anaemic (red cell count: 3970000 per mm3), gamma GT: 68 U/I.
1,0-
0.3-
-6
Material and Methods A study of the significance of low maintenance doses (Tabs. 1 a, b) of thioridazine in ten older psychiatric patients with a very long history of hospitalisation (mean 32 years) was started. Their overall clinical condition is also shown in Tab. 1 (a, b). The following investigations were carried out in all the patients: blood sedimentation rate, haemoglobin, red cell count, white cell count plus differential film, alkaline phosphatase, serum glutamate - oxalate transaminase (SGOT), serum glutamate - pyruvate transaminase (SGPT), lactate dehydrogenase (LDH), bilirubin, gamma glutamyl transpeptidase (gamma GT), cholesterol and total triglycerides. Two groups of five patients were selected, a drugwithdrawal group and a drug-maintained group. In the drug-withdrawal group the maintenance dose was halved after one month, halved again after two months, and after three months all psychoactive medication was discontinued. In the drug-maintained group no change in medication was made throughout the entire study (eight months); this report only contains the results for the first three months. During the period of investigation fasting blood samples were taken on the 10 th and 20 th day of each month. On the 10 th day of each month further blood samples were taken 3 - 7 and 11 h after the last dose. Selective chemical analyses were done using a combination of thin-layer chromatographic separation and fluorometric activation of thioridazine and its metabolites on a thin silica layer [1].
Plasma Level of Thioridazine and Its Metabolites
Time of Blood Samples K
0,03"
6
da
Fig. 1. Plasma levels after thioridazine 75 mg in the morning (patient Hu D). The different compounds shown are: o = thioridazine (T); • = mesoridazine (T2SO); [] = sulphoridazine (T2SOz); + = unidentified metabolite; = thioridazine-ring-sulphoxide(T5SO)
On the 10 th day of each of the first three months, blood samples were taken from ten psychiatric patients: fasting (Co) and three (C3), seven (C7) and eleven (Ctl) hours after the last dose. On the 10 th day of the third month a final sample was taken 23 hours after (C23) the last dose of thioridazine. 114 blood samples were obtained; on 16 occasions no sample was obtained as the patient refused to cooperate. The daily variation in the plasma-level can be expressed as Ct/C o. This quotient was not reproducible within individuals, so, to obtain a global impression of the daily variation in Ct/Co, the mean of all values in one time-interval was calculated. T h e results (Tab. 2) show that the daily variation was greatest at C3/Co for thioridazine (2.10 rag/l), but the variation was less marked for the sum of
R, G. Muusze and F. A. J. Vanderheereu: Thioridazine Plasma Levels II
143
TabLe 2. Ratio of plasma levels and variation in the mean ratio of the metabolites as a function of the time of blood-sampling. Means of data based on plasma levels from 10 older patients on low maintenance doses of thioridazine (50-200 mg/day). Time (h) after morning dose
0 3 7 11 23
Mean ratio (_+ S. D.) of plasma levels Ct/Coa
Mean ratio of thioridazine and metabolites
Thioridazine
T
T2SO
T2SO z
%
%
15 [] 16 14 13
27 28 28 28 26
Sum of "T a metabolites"
1.00
[2.10 -- 0.601 1.30 + 0.41 0.94 + 0.27 0.70 + 0.43
1.00 1.34 1.15 0.96 0.68
+ + + +
0.29 0.31 0.30 0.20
T5SO
%
Unidentiffed %
11 9 11 11 11
24 21 23 23 25
23 20 22 24 25
%
a Ct = plasma level at the time of sampling, C o = fasting plasma level Total number of blood samples N = 114.
Table 3. Mean average plateau level (rag/l) of thioridazine and the sum of "thioridazine plus metabolites" Patient
Daily dose thioridazine
AP PH HeD DF HuD PL GS LL
Thioridazine
Sum "T + Metabolites"
Mean average
Mean fasting
(rag)
plateaUlevel C;l (mg/1)
plasmalevel CO (mg/1)
200 150 150 150 150 150 t00 100
0.15 0.27 0.35 0.25 0.26 0.13 0.16 0.09
0.12 0.23 0.30 0.18 0.19 0,07 0.10 0.07
(W)
(W) (W) (W)
Mean ratio "~o
1.3 1.2 1.2 1.4 1.4 1.9 1.6 1.3
Mean average plateau level ~-pl (rag/l)
Mean fasting plasma level Cpl (mg/1)
Mean ratio
1.08 1.67 1.66 1.22 1.16 0.76 0.97 0.53
1.07 1,62 1.50 1.04 1,14 0.59 0.85 0.53
1.0 1.0 1.1 1.2 1.0 1.3 1,1 1.0
The mean average plateau level (Cpl) is the mean of three determinations of Cpt. C-o in the drug-withdrawal group (W) during dose period 1 is calculated with the aid of the mean relative average plateau level (Cpj/mg/kg.) Correlation coefficients between Co and Cpl are: for thioridazine 0.961; t = 15.448; P < 0.001 and for " T + metabolites" 0.956; t = 15.71; P < 0.001
thioridazine plus metabolites. An individual example is shown in Fig. 1 and Tab. 2. Only the daily variation in the percentage of thioridazine showed a significant peak (Table 2). Taking a blood sample before the patient's daily routine had begun, was the most practical and least troublesome manoeuvre. It is advantageous, however, to obtain the average plateau level (Cp0 [2], which can be calculated if a series of blood samples is taken on one day. The area under the concentration-time curve (AUC) is calculated by the trapezioid rule, in this case with four blood samples: AUCo_11 hr~ = 1/2 (C O + C3) • 3 + (C 3 + C7) " 4 + ( C 7 -1- C l l ) • 4 The average plateau concentration Cp~ is: Cpl = A . U . C . (t = l l h ) t
During the first three months of the study, the Cpl was calculated three times for eight patients; patients W. P. and F. D. did not cooperate on all occasions (Tab. 3). There was an intra-individual correlation between the fasting plasma level (Co) and the average plateau concentration (Cp¢ Tab. 3) for thioridazine and the sum of thioridazine plus metabolites; mean values are shown in Tab. 3. For thioridazine the quotient Cpl/Co showed an inter-individual variation of 1.2 to 1.9; for the sum of thioridazine plus metabolites the variation was much less being 1.0 to 1.4. Because of the correlation between Co and Cp~, it might be concluded that there was no need to determine Cpl in clinical studies. The inter-individual differences in the absolute value of the fasting plasma level (Tab. 3) were much greater than the inter-individual
144
R . G . Muusze and F. A. J. Vanderheeren: Thioridazine Plasma Levels II
Table 4. Correlation between thioridazine dose during the different dose periods and fasting plasma level of thioridazine (T) or the sum of thioridazine plus metabolites (T + M) in the drug-withdrawal group Patient
Thioridazine dose during the first dose period
Compound
Na
Correlation coefficient
Student's t-test
Significance P
DF
150 mg
T T + M
6
0.756 0.829
2.307 2.960
< 0.t < 0.05
AP
200 mg
T T + M
6
0.855 0.962
3.301 7.085
< 0.05 < 0.005
FD
50 mg
T T + M
6
0.958 0.877
6.713 3.645
< 0.005 < 0.025
GS
100 mg
T T + M
6
0.946 0.981
5.858 10.I98
< 0.005 < 0.001
PL
150 mg
T T + M
4
0.990 0.993
10.090 12.038
< 0.01 < 0.01
N = number of determinations
Table 5, Mean a fasting plasma levels of thioridazine and four metabolites in ten psychiatric patients on longterm thioridazine therapy Thioridazine Patient
Thioridazine daily dose b (mg)
AP PH HeD DF HuD PL GS WP LL FD
200 150 150 150 150 150 100 100 100 50
(W)
(W) (W) (W)
(W)
Average
Metabolites
Mean rel. plasma level mg/1 mg/kg
rel. S.D. %
Mean plasma level mg/l
0.038 0.099 0.147 0.107 0.091 0,026 0.084 0.083 0.064 0.041
13 22 9 30 21 12 42 34 21 20
0.13 0.22 0.31 0.21 0,18 0.07 0.10 0.14 0.08 0.03
0.078
22
mean plasma level rag/1 T2SO
T2SO 2
T5SO
Un ~
0.24 0.33 0.49 0.25 0.30 0,13 0.23 0.25 0.t9 0.09
0.10 0.13 0.21 0.08 0.11 0.06 0.10 0.11 0.08 0.05
0.33 0.48 0.25 0.34 0A9 0.17 0.24 0.19 0.13 0.03
0.31 0.42 0.32 0.28 0.24 0.18 0.23 0.21 0.15 0.04
" q h e mean plasma level in the drug-maintained group is the mean of six determinations. The mean plasma level in the drug-withdrawal group is calculated with the aid of the mean relative plasma Ievel. b The patients with doses indicated with "(W)" belonged to the drug-withdrawal group. c Un = unidentified metabolite.
differences in Cpl/CSo. So the determination of thioridazine and its metabolites before the morning dose of thioridazine (Co) could be taken as a reliable parameter in clinical studies.
Intra-Individual Relationship between Lower Doses of Thioridazine and Plasma Level None of the five patients in the drug-withdrawal group relapsed on reduction of the dose of thioridazine during the first three months of this study. During this time six fasting blood samples were taken, two in each
dose-period, and an intra-individual correlation between dose and plasma level (of thioridazine or the sum of thioridazine plus metabolites) was demonstrated (Tab. 4). It must be kept in mind that the relationship was proved only in a particular group of patients, comprising of aged patients with chronic disease and a long history of phenothiazine treatment. The intra-individual relationship between dose and plasma level has already been used in Table 3 for calculation of the mean average plateau level (Cp0 and the mean fasting plasma level (Co) in the drug-withdrawal-group (Tab.
4).
R. G. Muusze and F. A. J. Vanderheeren: Thioridazine PlasmaLevelsII In younger patients on higher doses of thioridazine, de Jonghe et al. [3] were unable to demonstrate any intra-individual correlation between dose and plasma level of the sum of thioridazine plus metabolites.
Inter-Individual Relationship between Lower Doses of Thioridazine and Plasma Level Contrary to two other investigators [4, 5], no inter-individual relationship between dose and plasma level was found in this group of elderly patients. The differences may be attributed to several factors, including a. inter-individual differences in age (range 49-79y) b. additional medication c. disease state. There was no correlation between mean relative plasma level of thioridazine (Tab. 5) and age, as suggested by Mgtrtensson and Roos [4]. Buyze et al. [6] showed the influence of additional medication on the plasma level of thioridazine; a mean reduction by a factor of 1.4 was observed. The ten patients in the present study can be divided into two groups: six patients without additional medication (DF, FD, HeD, PH, HuD and WP) and four patients with additional medication (AP, G. S., PL, EL) (Table 1 a, b). There was a difference in the average mean relative plasma level of both groups, respectively, 0.087 mg/1 and 0.064 ~ , which is about a factor of i.4. The lower levels of PL and LL may be due to liver-enzyme induction by phenobarbital, which would be consistent with the higher value of gammaGT (34 and 68 U/lit.)
Reliability of the Individual Plasma Level Six fasting blood samples were taken from each patient ( N = 10) during the first three months of the study. In the drug-maintained group (N = 5) the intra-individual standard deviation could be calculated directly from the plasma level, but in the drug-withdrawal group the dose and therefore the plasma level was halved each month. Due to the relationship between dose and plasmalevel in the drug-withdrawal group, an intra-individual standard deviation had to be calculated from a dose-independent parameter. The relative plasma level (Crd) can be used: CreL =
plasma-level (mg/1) dose (mg/kg)
From six individual relative plasma levels the standard deviation was calculated (Tab. 5). The mean
145
relative standard deviation was 22%, range 9-44%. Inter-individual differences in the mean relative plasma level of thioridazine gave a first impression of differences in bio-availability. There was a factor of 5.6 between the highest and lowest thioridazine plasma levels. Moreover, these values (0.026 and 0.147 rag/1 mg/kg) belonged to subjects in the same dose group (150 mg/day).
Individual Nature of the Percentages of Psycho-Active Compounds The most complete information about plasma levels after oral dosage of thioridazine has been given as five separate figures, which represent the concentrations of thioridazine and four metabolites (Tab. 5). However, some of the figures can be combined, for example in one value for the total concentration of the sum of active compounds (Tab. 6). The percentage contribution of active compounds to the total sum of thioridazine plus metabolites showed an inter-individual range of 43-74%. There was only a small inter-individual difference in the percentage composition of the various active compounds.
Elimination Kinetics after Multiple Doses 114 bloodsamples were taken from 10 patients 0, 3, 7, 11 and 23 hours after the last dose of thioridazine. As stated in the section "Times of blood samples", the rate of disappearance of thioridazine was not reproducible within individual patients. However, the mean of all the data gives an impression of a bi-exponential decay of the thioridazine concentration: a mean "early disappearance half-life" of 5 h (during 3-7 h time interval after the dose), and a mean "late disappearance half-life" of 26 h (during 11-23 h time interval after the dose; [40 . In a further group of five older psychiatric patients, the disappearance was studied for four days after termination of long-term thioridazine treatment. Blood samples were taken 3, 27, J 1, and 75 h after the last dose. A four point determination of the half-life of thioridazine and four metabolites was made according to the method of the least squares (Tab. 7). As there were marked intra-individual differences between the various time-intervals (3-27 h, 27-51 and 51-75 h), the range of half-lives has been similarly subdivided (Fig. 2). For reliable determination of plasma concentration of thioridazine and metabolites (Fig. 2) on the third and fourth day after termination of thioridazine treatment, a sensitive selective chemical method is needed.
146
R . G . M u u s z e and F. A. J. Vanderheeren: Thioridazine Plasma Levels II
Table 6. M e a n a fasting plasma levels of thioridazine and metabolites and the percentage composition of the active c o m p o u n d s in ten psychiatric patients on long term thioridazine therapy Plasma level Patient
AP PH HeD DF HuD PL GS WP LL FD
Daily dose b thioridazine mg
S u m of "'T + metabolites" mg/l
S u m of active compounds
200 150 150 150 150 150 100 100 100 50
1.10 1.59 1.58 1.18 1.02 0.61 0.90 0.89 0.63 0.23
1.10 0.68 1.01 0.54 0.59 0.26 0.43 0.50 0.35 0.17
(W)
(W) (W) (W)
(W)
Percentage active compounds
mg/l
Average
Percent composition of the active compounds T
T2SO
T2SO 2
43 43 64 46 58 43 48 56 56 74
28 32 31 39 31 27 23 28 23 18
52 49 49 46 51 50 53 50 54 53
21 19 20 15 18 23 24 22 23 29
53
28
51
21
" T h e m e a n plasma level in the drug-maintained group is the m e a n of six determinations. T h e m e a n plasma level in the drug-withdrawal group is calculated with the aid of the m e a n relative plasma level. b Patients with doses indicated with " ( W ) " belonged to the drug-withdrawal group.
Table 7. A p p a r e n t half-life of disappearance (t 1/2): M e a n s + S. D. of thioridazine and metabolites following termination of long-term treatment Patient
~
T
T2SO
T2SO 2
T5SO
Un
t 1/2 (h) CE 1 x 200 m g thioridazine 49 kg 66 years
tl/2
15+2
11+ 1
21+4
21+2
18_+1
range
14 - 24
11 - 24
13 - 58
16 - 25
15 -
EP 3 x 50 m g thioridazine 68 kg 69 years
tl/2
15+ 1
21+1
29+6
38+3
32+2
range
14 - 22
19 - 25
18 - 43
34 - 49
27 - 36
EG 3 × 50 m g thioridazine 80 kg 70 years
tl/2
28--+2
31_+3
38+4
48+_ 14
45+6
range
24 - 32
21 - 38
27 - 41
24 - 100
29 - 80
MB 3 x 50 m g thioridazine 86 kg 58 years
tl/2
23+6
30+7
54+30
42_+15
33+8
range
16 - 41
22 - 48
22 - 200
27 -
23 - 554
FB 1 × 100 m g thioridazine 70 kg 56 years
t 1/2
27 ± 4
21 + 2
43 + 8
29 + 2
28 ± 2
range
20 - 41
18 - 26
31 - 59
23 - 42
25 - 35
" t 1/2 is a four-point determination (3 - 27 - 51 - 75 h) according to the least squares method. T h e range is the variation of the three two-point determinations (3 - 27 h, 27 - 51 h and 51 - 75 h).
101
18
R. G. Muusze and F. A. J. Vanderheeren: Thioridazine Plasma Levels II 1.0-
147
ad 1: The metabolic characteristics can only be measured by a selective method, which assays at least the three psycho-active compounds: thioridazine, mesoridazine and sulphoridazine. Due to the stability of this characteristic, such a specific analysis need only be done twice during a clinical study. ad 2: The individual plasma level is very variable, so to obtain a reliable mean the plasma level should be measured 2 - 4 times a month. When thioridazine is the only drug given, an non-selective chemical method [7, 8] can be used. Possibly, the sum of thioridazine plus metabolites [3, 5, 9] is a more important parameter for clinical studies than the plasma concentration of thioridazine alone [4].
0.3
E 0.1 -
Acknowledgements. We are indebted to Mrs. A. J. Visser-Van Der Weel and Mrs. C. Van Ham-Vesters for their skilled technical assistence.
0.03-
References
$ ; /
2'7
¢5
Time offer dose {hours}
Fig. 2. Plasma levels of thioridazine and four metabolites after
termination of long-term thioridazine treatment (3 × 50 rag/day). Patient: age = 69 years, weight 68 kg, diagnosis: schizophrenia. o = thioridazine (T); • = mesoridazine (T2SO); [] = sulphoridazine (T2SO2); + = unidentified metabolite; • = thioridazine-ring-sulphoxide (T5SO)
The combination of T. L. C. separation and fluorimetric activation on silica gel yields detection limits in plasma of 1-4 ng/ml for the various compounds, so plasma concentrations between 10-50 ng/ml on the third and fourth day could be measured reliably.
Conclusion Reliable information about the plasma level of thioridazine and metabolites can be obtained from blood samples taken before the morning dose of thioridazine. Two important parameters should be measured in clinical studies on thioridazine: 1. Individual characteristics of the metabolic pattern. 2. The plasma level of the sum of thioridazine plus metabolites.
1. Muusze, R. G.: Analysis of thioridazine and some of its metabolites in blood by liquid chromatography. Thesis, Amsterdam 1975 2. Van Rossum, J. M., Tomey, A. H. J. M.: Multicompartmentkinetics and the accumulation plateau. Arch. int. Pharmacodyn. 188, 200-203 (1970) 3. De Jonghe, F. E. R. E. R., Van Der Helm, H. J., Schalken, H. F. A., Thiel, J. H.: Therapeutic effect and plasma level of thioridazine. Acta Psychiat. scand. 49, 535-545 (1973) 4. Mhrtensson, E., Roos, B. E.: Serum levels of thioridazine in psychiatric patients and healthy volunteers. Europ. J. clin. Pharmacol. 6, 181-186 (1973) 5. Bergling, R., Mj6rndal, T., Oreland, L., Rapp, W., Wold, S.: Plasma levels and clinical effect of thioridazine and thiothixene. J. clin. Pharmacol. 15, 178-186 (1975) 6. Buyze, G., Egberts, P. F. C., Muusze, R. G., Poslavsky, A.: Blood levels of thioridazine and some of its metabolites in schizophrenic patients. Psychiat. Neurol. Neurochir. 76, 229-239 (1973) 7. Pacha, W. L.: A method for the fluorimetric determination of thioridazine or mesoridazine in plasma. Experientia (Basel) 25, 103-104 (1969) 8. Raglan& J. B., Kinross-Wright, V. J., Ragland, R. S.: Determination of phenothiazines in biological samples. Anal. Biochem. 12, 60-69 (1965) 9. Klein, H. E., Chandra, O., Matussek, N.: Therapeutische Wirkung und Plasmaspiegel von Thioridazin bei schizophrenen Patienten. Pharmakopsychiat. 8, 122-131 (1975)
Received: April 20, 1976, and in revised form: August 27, 1976, accepted: September 2, 1976 Dr. R. G. Muusze Psychiatric Clinic "Het St.-Jorisgasthuis" St.-Jorisweg Delft
The Netherlands
Europ. J. clin. Pharmacol. 11,141-147 (1977)
© by Springer Verlag 1977
Plasma Levels and Half Lives of Thioridazine and Some of Its Metabolites II. Low Doses in Older Psychiatric Patients R. G. Muusze 1 and F. A. J. Vanderheeren 2 1Psychiatric Clinic Delft, Netherlands, and 2 Department of Psychiatry, University of Ghent, Ghent, Belgium
Summary. Plasma-levels of thioridazine, mesoridazine, sulphoridazine and two other metabolites were determined in ten older chronic psychotic patients on thioridazine therapy. The plasma-level before the morning dose of thioridazine was the most reliable parameter for clinical studies. An intra-individual relationship between lower doses of thioridazine and plasma-levels was found. The percentage contribution of psychoactive compounds to the total sum of "thioridazine plus metabolites" ranged from 43-74%. The mean "early disappearance half-life" of thioridazine was 5 hours, and its mean "late disappearance half-life" was 26 hours.
Table la. Clinical details and treatment of patients in the drugwithdrawal group Patient Age
years kg
Daily dose (mg) thioridazine
DF
56
76
thioridazine
2 × 75
AP
68
59
thioridazine cyproheptadine orphenadrine vitamin C vitamincombination a
2 × 100
thioridazine
2 × 25
thioridazine distigminebromide
2 x 50
thioridazine phenobarbitone
2 × 75
FD
Key words: Phenothiazine, thioridazine, plasma level, metabolic pattern, half life, man, schizophrenia.
Weight Drug
GS
PL
57 73
74
72 85
54
other drugs
2x4 2x50 3x50
3x5 3 x75
Mean daily dose of thioridazine 130 mg
In this investigation, certain pharmacological and pharmacokinetic parameters of thioridazine and four metabolites were determined in a population of ten older chronically psychotic patients, who received a low long term maintenance therapy with thioridazine (50-200 rag/day). The influence of the time of blood sampling on the plasma level, the reliability and pharmacological meaning of plasma levels and the relationship between dose and plasma level are all parameters of importance, and they should be known before the relationship between plasma level and clinical effect of a drug is studied.
Vitamin combination: Davitamon 10 (one daily) contains: retinol palmitate 1000 IU, thiamine mononitrate 0,5 rag, riboflavine 0,5 rag, nicotinamide 5 mg, pyridoxine chloride 0,2 mg, cyanocobalamine 0,5 mcg, calcium pantothenate 1 mg, ascorbic acid 20 mg, ergocalciferol 400 IU, tocoferol-alpha-acetate 1 mg). The same patient also received hydroxocobalamine 1000 mcg monthly. DF: AP: FD: GS: PL:
formerly pulmonary tuberculosis, now emphysema, normal blood values vitamin B12 deficiency, normal blood values diabetes mellitus, treated with diet; normal blood values right bundle branch block on electrocardiogram, normal blood values formerly pulmonary tuberculosis, at present diabetes mellitus, treated with diet; blood: red cell count 3 770 000 per mm 3, gamma GT 34 U/l, cholesterol 7.9 mmol/1
142
R.G. Muusze and F. A. J. Vanderheeren: Thioridazine Plasma Levels II
Table lb. Clinical details and treatment of patients in the drngmaintained group Patient Age
Weight Drug
thioridazine other drugs
years kg HeD PH HuD LL
WP
49 66 54 70
71 67 75 78
79
62
Daily dose (mg)
thioridazine thioridazine thioridazine thioridazine phenytoin phenobarbitone cyclandelate thioridazine
2 × 75 2 × 75 2 × 75 2 × 50 3 × 50 3 × 50 1 x 200 2 × 50
mean daily dose of thioridazine 130 mg Patients HeD, PH, HuD and WP: healthy, normal blood values. Patient LL: mild chronic bronchitis, slightly anaemic (red cell count: 3970000 per mm3), gamma GT: 68 U/I.
1,0-
0.3-
-6
Material and Methods A study of the significance of low maintenance doses (Tabs. 1 a, b) of thioridazine in ten older psychiatric patients with a very long history of hospitalisation (mean 32 years) was started. Their overall clinical condition is also shown in Tab. 1 (a, b). The following investigations were carried out in all the patients: blood sedimentation rate, haemoglobin, red cell count, white cell count plus differential film, alkaline phosphatase, serum glutamate - oxalate transaminase (SGOT), serum glutamate - pyruvate transaminase (SGPT), lactate dehydrogenase (LDH), bilirubin, gamma glutamyl transpeptidase (gamma GT), cholesterol and total triglycerides. Two groups of five patients were selected, a drugwithdrawal group and a drug-maintained group. In the drug-withdrawal group the maintenance dose was halved after one month, halved again after two months, and after three months all psychoactive medication was discontinued. In the drug-maintained group no change in medication was made throughout the entire study (eight months); this report only contains the results for the first three months. During the period of investigation fasting blood samples were taken on the 10 th and 20 th day of each month. On the 10 th day of each month further blood samples were taken 3 - 7 and 11 h after the last dose. Selective chemical analyses were done using a combination of thin-layer chromatographic separation and fluorometric activation of thioridazine and its metabolites on a thin silica layer [1].
Plasma Level of Thioridazine and Its Metabolites
Time of Blood Samples K
0,03"
6
da
Fig. 1. Plasma levels after thioridazine 75 mg in the morning (patient Hu D). The different compounds shown are: o = thioridazine (T); • = mesoridazine (T2SO); [] = sulphoridazine (T2SOz); + = unidentified metabolite; = thioridazine-ring-sulphoxide(T5SO)
On the 10 th day of each of the first three months, blood samples were taken from ten psychiatric patients: fasting (Co) and three (C3), seven (C7) and eleven (Ctl) hours after the last dose. On the 10 th day of the third month a final sample was taken 23 hours after (C23) the last dose of thioridazine. 114 blood samples were obtained; on 16 occasions no sample was obtained as the patient refused to cooperate. The daily variation in the plasma-level can be expressed as Ct/C o. This quotient was not reproducible within individuals, so, to obtain a global impression of the daily variation in Ct/Co, the mean of all values in one time-interval was calculated. T h e results (Tab. 2) show that the daily variation was greatest at C3/Co for thioridazine (2.10 rag/l), but the variation was less marked for the sum of
R, G. Muusze and F. A. J. Vanderheereu: Thioridazine Plasma Levels II
143
TabLe 2. Ratio of plasma levels and variation in the mean ratio of the metabolites as a function of the time of blood-sampling. Means of data based on plasma levels from 10 older patients on low maintenance doses of thioridazine (50-200 mg/day). Time (h) after morning dose
0 3 7 11 23
Mean ratio (_+ S. D.) of plasma levels Ct/Coa
Mean ratio of thioridazine and metabolites
Thioridazine
T
T2SO
T2SO z
%
%
15 [] 16 14 13
27 28 28 28 26
Sum of "T a metabolites"
1.00
[2.10 -- 0.601 1.30 + 0.41 0.94 + 0.27 0.70 + 0.43
1.00 1.34 1.15 0.96 0.68
+ + + +
0.29 0.31 0.30 0.20
T5SO
%
Unidentiffed %
11 9 11 11 11
24 21 23 23 25
23 20 22 24 25
%
a Ct = plasma level at the time of sampling, C o = fasting plasma level Total number of blood samples N = 114.
Table 3. Mean average plateau level (rag/l) of thioridazine and the sum of "thioridazine plus metabolites" Patient
Daily dose thioridazine
AP PH HeD DF HuD PL GS LL
Thioridazine
Sum "T + Metabolites"
Mean average
Mean fasting
(rag)
plateaUlevel C;l (mg/1)
plasmalevel CO (mg/1)
200 150 150 150 150 150 t00 100
0.15 0.27 0.35 0.25 0.26 0.13 0.16 0.09
0.12 0.23 0.30 0.18 0.19 0,07 0.10 0.07
(W)
(W) (W) (W)
Mean ratio "~o
1.3 1.2 1.2 1.4 1.4 1.9 1.6 1.3
Mean average plateau level ~-pl (rag/l)
Mean fasting plasma level Cpl (mg/1)
Mean ratio
1.08 1.67 1.66 1.22 1.16 0.76 0.97 0.53
1.07 1,62 1.50 1.04 1,14 0.59 0.85 0.53
1.0 1.0 1.1 1.2 1.0 1.3 1,1 1.0
The mean average plateau level (Cpl) is the mean of three determinations of Cpt. C-o in the drug-withdrawal group (W) during dose period 1 is calculated with the aid of the mean relative average plateau level (Cpj/mg/kg.) Correlation coefficients between Co and Cpl are: for thioridazine 0.961; t = 15.448; P < 0.001 and for " T + metabolites" 0.956; t = 15.71; P < 0.001
thioridazine plus metabolites. An individual example is shown in Fig. 1 and Tab. 2. Only the daily variation in the percentage of thioridazine showed a significant peak (Table 2). Taking a blood sample before the patient's daily routine had begun, was the most practical and least troublesome manoeuvre. It is advantageous, however, to obtain the average plateau level (Cp0 [2], which can be calculated if a series of blood samples is taken on one day. The area under the concentration-time curve (AUC) is calculated by the trapezioid rule, in this case with four blood samples: AUCo_11 hr~ = 1/2 (C O + C3) • 3 + (C 3 + C7) " 4 + ( C 7 -1- C l l ) • 4 The average plateau concentration Cp~ is: Cpl = A . U . C . (t = l l h ) t
During the first three months of the study, the Cpl was calculated three times for eight patients; patients W. P. and F. D. did not cooperate on all occasions (Tab. 3). There was an intra-individual correlation between the fasting plasma level (Co) and the average plateau concentration (Cp¢ Tab. 3) for thioridazine and the sum of thioridazine plus metabolites; mean values are shown in Tab. 3. For thioridazine the quotient Cpl/Co showed an inter-individual variation of 1.2 to 1.9; for the sum of thioridazine plus metabolites the variation was much less being 1.0 to 1.4. Because of the correlation between Co and Cp~, it might be concluded that there was no need to determine Cpl in clinical studies. The inter-individual differences in the absolute value of the fasting plasma level (Tab. 3) were much greater than the inter-individual
144
R . G . Muusze and F. A. J. Vanderheeren: Thioridazine Plasma Levels II
Table 4. Correlation between thioridazine dose during the different dose periods and fasting plasma level of thioridazine (T) or the sum of thioridazine plus metabolites (T + M) in the drug-withdrawal group Patient
Thioridazine dose during the first dose period
Compound
Na
Correlation coefficient
Student's t-test
Significance P
DF
150 mg
T T + M
6
0.756 0.829
2.307 2.960
< 0.t < 0.05
AP
200 mg
T T + M
6
0.855 0.962
3.301 7.085
< 0.05 < 0.005
FD
50 mg
T T + M
6
0.958 0.877
6.713 3.645
< 0.005 < 0.025
GS
100 mg
T T + M
6
0.946 0.981
5.858 10.I98
< 0.005 < 0.001
PL
150 mg
T T + M
4
0.990 0.993
10.090 12.038
< 0.01 < 0.01
N = number of determinations
Table 5, Mean a fasting plasma levels of thioridazine and four metabolites in ten psychiatric patients on longterm thioridazine therapy Thioridazine Patient
Thioridazine daily dose b (mg)
AP PH HeD DF HuD PL GS WP LL FD
200 150 150 150 150 150 100 100 100 50
(W)
(W) (W) (W)
(W)
Average
Metabolites
Mean rel. plasma level mg/1 mg/kg
rel. S.D. %
Mean plasma level mg/l
0.038 0.099 0.147 0.107 0.091 0,026 0.084 0.083 0.064 0.041
13 22 9 30 21 12 42 34 21 20
0.13 0.22 0.31 0.21 0,18 0.07 0.10 0.14 0.08 0.03
0.078
22
mean plasma level rag/1 T2SO
T2SO 2
T5SO
Un ~
0.24 0.33 0.49 0.25 0.30 0,13 0.23 0.25 0.t9 0.09
0.10 0.13 0.21 0.08 0.11 0.06 0.10 0.11 0.08 0.05
0.33 0.48 0.25 0.34 0A9 0.17 0.24 0.19 0.13 0.03
0.31 0.42 0.32 0.28 0.24 0.18 0.23 0.21 0.15 0.04
" q h e mean plasma level in the drug-maintained group is the mean of six determinations. The mean plasma level in the drug-withdrawal group is calculated with the aid of the mean relative plasma Ievel. b The patients with doses indicated with "(W)" belonged to the drug-withdrawal group. c Un = unidentified metabolite.
differences in Cpl/CSo. So the determination of thioridazine and its metabolites before the morning dose of thioridazine (Co) could be taken as a reliable parameter in clinical studies.
Intra-Individual Relationship between Lower Doses of Thioridazine and Plasma Level None of the five patients in the drug-withdrawal group relapsed on reduction of the dose of thioridazine during the first three months of this study. During this time six fasting blood samples were taken, two in each
dose-period, and an intra-individual correlation between dose and plasma level (of thioridazine or the sum of thioridazine plus metabolites) was demonstrated (Tab. 4). It must be kept in mind that the relationship was proved only in a particular group of patients, comprising of aged patients with chronic disease and a long history of phenothiazine treatment. The intra-individual relationship between dose and plasma level has already been used in Table 3 for calculation of the mean average plateau level (Cp0 and the mean fasting plasma level (Co) in the drug-withdrawal-group (Tab.
4).
R. G. Muusze and F. A. J. Vanderheeren: Thioridazine PlasmaLevelsII In younger patients on higher doses of thioridazine, de Jonghe et al. [3] were unable to demonstrate any intra-individual correlation between dose and plasma level of the sum of thioridazine plus metabolites.
Inter-Individual Relationship between Lower Doses of Thioridazine and Plasma Level Contrary to two other investigators [4, 5], no inter-individual relationship between dose and plasma level was found in this group of elderly patients. The differences may be attributed to several factors, including a. inter-individual differences in age (range 49-79y) b. additional medication c. disease state. There was no correlation between mean relative plasma level of thioridazine (Tab. 5) and age, as suggested by Mgtrtensson and Roos [4]. Buyze et al. [6] showed the influence of additional medication on the plasma level of thioridazine; a mean reduction by a factor of 1.4 was observed. The ten patients in the present study can be divided into two groups: six patients without additional medication (DF, FD, HeD, PH, HuD and WP) and four patients with additional medication (AP, G. S., PL, EL) (Table 1 a, b). There was a difference in the average mean relative plasma level of both groups, respectively, 0.087 mg/1 and 0.064 ~ , which is about a factor of i.4. The lower levels of PL and LL may be due to liver-enzyme induction by phenobarbital, which would be consistent with the higher value of gammaGT (34 and 68 U/lit.)
Reliability of the Individual Plasma Level Six fasting blood samples were taken from each patient ( N = 10) during the first three months of the study. In the drug-maintained group (N = 5) the intra-individual standard deviation could be calculated directly from the plasma level, but in the drug-withdrawal group the dose and therefore the plasma level was halved each month. Due to the relationship between dose and plasmalevel in the drug-withdrawal group, an intra-individual standard deviation had to be calculated from a dose-independent parameter. The relative plasma level (Crd) can be used: CreL =
plasma-level (mg/1) dose (mg/kg)
From six individual relative plasma levels the standard deviation was calculated (Tab. 5). The mean
145
relative standard deviation was 22%, range 9-44%. Inter-individual differences in the mean relative plasma level of thioridazine gave a first impression of differences in bio-availability. There was a factor of 5.6 between the highest and lowest thioridazine plasma levels. Moreover, these values (0.026 and 0.147 rag/1 mg/kg) belonged to subjects in the same dose group (150 mg/day).
Individual Nature of the Percentages of Psycho-Active Compounds The most complete information about plasma levels after oral dosage of thioridazine has been given as five separate figures, which represent the concentrations of thioridazine and four metabolites (Tab. 5). However, some of the figures can be combined, for example in one value for the total concentration of the sum of active compounds (Tab. 6). The percentage contribution of active compounds to the total sum of thioridazine plus metabolites showed an inter-individual range of 43-74%. There was only a small inter-individual difference in the percentage composition of the various active compounds.
Elimination Kinetics after Multiple Doses 114 bloodsamples were taken from 10 patients 0, 3, 7, 11 and 23 hours after the last dose of thioridazine. As stated in the section "Times of blood samples", the rate of disappearance of thioridazine was not reproducible within individual patients. However, the mean of all the data gives an impression of a bi-exponential decay of the thioridazine concentration: a mean "early disappearance half-life" of 5 h (during 3-7 h time interval after the dose), and a mean "late disappearance half-life" of 26 h (during 11-23 h time interval after the dose; [40 . In a further group of five older psychiatric patients, the disappearance was studied for four days after termination of long-term thioridazine treatment. Blood samples were taken 3, 27, J 1, and 75 h after the last dose. A four point determination of the half-life of thioridazine and four metabolites was made according to the method of the least squares (Tab. 7). As there were marked intra-individual differences between the various time-intervals (3-27 h, 27-51 and 51-75 h), the range of half-lives has been similarly subdivided (Fig. 2). For reliable determination of plasma concentration of thioridazine and metabolites (Fig. 2) on the third and fourth day after termination of thioridazine treatment, a sensitive selective chemical method is needed.
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R . G . M u u s z e and F. A. J. Vanderheeren: Thioridazine Plasma Levels II
Table 6. M e a n a fasting plasma levels of thioridazine and metabolites and the percentage composition of the active c o m p o u n d s in ten psychiatric patients on long term thioridazine therapy Plasma level Patient
AP PH HeD DF HuD PL GS WP LL FD
Daily dose b thioridazine mg
S u m of "'T + metabolites" mg/l
S u m of active compounds
200 150 150 150 150 150 100 100 100 50
1.10 1.59 1.58 1.18 1.02 0.61 0.90 0.89 0.63 0.23
1.10 0.68 1.01 0.54 0.59 0.26 0.43 0.50 0.35 0.17
(W)
(W) (W) (W)
(W)
Percentage active compounds
mg/l
Average
Percent composition of the active compounds T
T2SO
T2SO 2
43 43 64 46 58 43 48 56 56 74
28 32 31 39 31 27 23 28 23 18
52 49 49 46 51 50 53 50 54 53
21 19 20 15 18 23 24 22 23 29
53
28
51
21
" T h e m e a n plasma level in the drug-maintained group is the m e a n of six determinations. T h e m e a n plasma level in the drug-withdrawal group is calculated with the aid of the m e a n relative plasma level. b Patients with doses indicated with " ( W ) " belonged to the drug-withdrawal group.
Table 7. A p p a r e n t half-life of disappearance (t 1/2): M e a n s + S. D. of thioridazine and metabolites following termination of long-term treatment Patient
~
T
T2SO
T2SO 2
T5SO
Un
t 1/2 (h) CE 1 x 200 m g thioridazine 49 kg 66 years
tl/2
15+2
11+ 1
21+4
21+2
18_+1
range
14 - 24
11 - 24
13 - 58
16 - 25
15 -
EP 3 x 50 m g thioridazine 68 kg 69 years
tl/2
15+ 1
21+1
29+6
38+3
32+2
range
14 - 22
19 - 25
18 - 43
34 - 49
27 - 36
EG 3 × 50 m g thioridazine 80 kg 70 years
tl/2
28--+2
31_+3
38+4
48+_ 14
45+6
range
24 - 32
21 - 38
27 - 41
24 - 100
29 - 80
MB 3 x 50 m g thioridazine 86 kg 58 years
tl/2
23+6
30+7
54+30
42_+15
33+8
range
16 - 41
22 - 48
22 - 200
27 -
23 - 554
FB 1 × 100 m g thioridazine 70 kg 56 years
t 1/2
27 ± 4
21 + 2
43 + 8
29 + 2
28 ± 2
range
20 - 41
18 - 26
31 - 59
23 - 42
25 - 35
" t 1/2 is a four-point determination (3 - 27 - 51 - 75 h) according to the least squares method. T h e range is the variation of the three two-point determinations (3 - 27 h, 27 - 51 h and 51 - 75 h).
101
18
R. G. Muusze and F. A. J. Vanderheeren: Thioridazine Plasma Levels II 1.0-
147
ad 1: The metabolic characteristics can only be measured by a selective method, which assays at least the three psycho-active compounds: thioridazine, mesoridazine and sulphoridazine. Due to the stability of this characteristic, such a specific analysis need only be done twice during a clinical study. ad 2: The individual plasma level is very variable, so to obtain a reliable mean the plasma level should be measured 2 - 4 times a month. When thioridazine is the only drug given, an non-selective chemical method [7, 8] can be used. Possibly, the sum of thioridazine plus metabolites [3, 5, 9] is a more important parameter for clinical studies than the plasma concentration of thioridazine alone [4].
0.3
E 0.1 -
Acknowledgements. We are indebted to Mrs. A. J. Visser-Van Der Weel and Mrs. C. Van Ham-Vesters for their skilled technical assistence.
0.03-
References
$ ; /
2'7
¢5
Time offer dose {hours}
Fig. 2. Plasma levels of thioridazine and four metabolites after
termination of long-term thioridazine treatment (3 × 50 rag/day). Patient: age = 69 years, weight 68 kg, diagnosis: schizophrenia. o = thioridazine (T); • = mesoridazine (T2SO); [] = sulphoridazine (T2SO2); + = unidentified metabolite; • = thioridazine-ring-sulphoxide (T5SO)
The combination of T. L. C. separation and fluorimetric activation on silica gel yields detection limits in plasma of 1-4 ng/ml for the various compounds, so plasma concentrations between 10-50 ng/ml on the third and fourth day could be measured reliably.
Conclusion Reliable information about the plasma level of thioridazine and metabolites can be obtained from blood samples taken before the morning dose of thioridazine. Two important parameters should be measured in clinical studies on thioridazine: 1. Individual characteristics of the metabolic pattern. 2. The plasma level of the sum of thioridazine plus metabolites.
1. Muusze, R. G.: Analysis of thioridazine and some of its metabolites in blood by liquid chromatography. Thesis, Amsterdam 1975 2. Van Rossum, J. M., Tomey, A. H. J. M.: Multicompartmentkinetics and the accumulation plateau. Arch. int. Pharmacodyn. 188, 200-203 (1970) 3. De Jonghe, F. E. R. E. R., Van Der Helm, H. J., Schalken, H. F. A., Thiel, J. H.: Therapeutic effect and plasma level of thioridazine. Acta Psychiat. scand. 49, 535-545 (1973) 4. Mhrtensson, E., Roos, B. E.: Serum levels of thioridazine in psychiatric patients and healthy volunteers. Europ. J. clin. Pharmacol. 6, 181-186 (1973) 5. Bergling, R., Mj6rndal, T., Oreland, L., Rapp, W., Wold, S.: Plasma levels and clinical effect of thioridazine and thiothixene. J. clin. Pharmacol. 15, 178-186 (1975) 6. Buyze, G., Egberts, P. F. C., Muusze, R. G., Poslavsky, A.: Blood levels of thioridazine and some of its metabolites in schizophrenic patients. Psychiat. Neurol. Neurochir. 76, 229-239 (1973) 7. Pacha, W. L.: A method for the fluorimetric determination of thioridazine or mesoridazine in plasma. Experientia (Basel) 25, 103-104 (1969) 8. Raglan& J. B., Kinross-Wright, V. J., Ragland, R. S.: Determination of phenothiazines in biological samples. Anal. Biochem. 12, 60-69 (1965) 9. Klein, H. E., Chandra, O., Matussek, N.: Therapeutische Wirkung und Plasmaspiegel von Thioridazin bei schizophrenen Patienten. Pharmakopsychiat. 8, 122-131 (1975)
Received: April 20, 1976, and in revised form: August 27, 1976, accepted: September 2, 1976 Dr. R. G. Muusze Psychiatric Clinic "Het St.-Jorisgasthuis" St.-Jorisweg Delft
The Netherlands
