haloperidol ratios in plasma: Polymorphism in Japanese psychiatric patients

111

Psychiatry Research. 3 I : I I I - I20 Elsevier

Reduced Haloperidol/Haloperidol Ratios in Plasma: Polymorphism in Japanese Psychiatric Patients Toshiyuki Someya, Saburo Takahashi, Morikazu Shibasaki, Tadanobu Inaba, Siu Wah Cheung, and Siu Wa Tang Received February IO, 1989; revised version received May 31. 1989; accepted July 21, 1989. Abstract. We measured plasma concentrations of haloperidol (HAL) and its metabolite, reduced haloperidol (RHAL), by high performance liquid chromatography (HPLC) in 45 Japanese psychiatric patients receiving HAL. Plasma levels of HAL had a highly positive correlation with daily dose per body weight. Plasma RHAL/HAL ratios had also a dose-dependent relationship, but their distribution was nonnormal and a bimodal pattern with an antimode at 0.7 was apparent by probit analysis. There were 8 subjects (18%) with high RHAL/ HAL ratios (mean = 1.26, SD = 0.41) and 37 subjects (82%) with low RHAL/HALratios(mean=0.42,SD=0.13). RHAL/HALratiosshowedlittle intraindividual variability (k 10.6%) while interindividual variability was large. This may suggest that pharmacogenetic factors are involved in the metabolism of HAL and RHAL. Key Words.

Body

weight,

schizophrenia,

neuroleptic

dose.

Antipsychotic drugs are widely used in psychiatric practice, and ethnic differences in their doses and tolerance have been suggested in countries with various ethnic groups (Lin and Finder, 1983). Potkin et al. (1984) reported in an international collaborative study that Chinese patients exhibited higher plasma levels of haloperidol (HAL) than Caucasians in the United States when both groups were maintained on the same fixed dose. lnterindividual differences in drug metabolism and polymorphisms have drawn attention in the 1980’s, and the presence of deficient metabolizers has been recognized for such drugs as debrisoquine, sparteine, mephenytoin, and desipramine (Jacqz et al., 1986). HAL is one of the most commonly prescribed neuroleptics and, since its metabolism is known to be simple, it can serve as a useful tool for pharmacokinetic research. It is inactivated through the pathway of carbon chain cleavage (Braun et al., 1967) or metabolized to its reduced metabolite, reduced haloperidol (RHAL), which was found in plasma from patients on HAL (Forsman and Larsson, 1978; Pape, 1981).

Toshiyuki Someya, M.D., is Instructor of Psychiatry; Saburo Takahashi, M.D., Ph.D.. is Professor and Chairman; and Morikazu Shibasaki, M.D., is Resident in Psychiatry, Shiga University of Medical Science. Tadanobu Inaba, Ph.D., is Associate Professor of Pharmacology, Universitv of Toronto. Siu Wah Cheung, B.Sc., is Research Assistant, Psychopharmacology Unit, Clarke Institute-of Psychiatry. Siu Wa Tang. M.B.. Ph.D., F.R.C.P.(C). is Director. Psvchopharmacolonv Unit. Clarke Institute of Psychiatry, and Associate Professor of Psychiatry and Pharmacology, U&ersity of Toronto. (Reprint requests to Dr. T. Someya, Department of Psychiatry, Shiga University of Medical Science, Seta Tsukinowacho, Otsu 520-21, Japan.) 0161781/90/$03.50

@ 1990 Elsevier Scientific Publishers Ireland

Ltd

112 The ratio of RHAL/HAL has drawn attention as an index of the activity of the enzyme that metabolizes HAL. RHAL/HAL ratios were reported to be lower in 21 Chinese subjects than the values found in Caucasians (Chang et al., 1987~). At present, however, it is not clear what the ratio represents or how it correlates with the clinical effects of HAL. We studied HAL and RHAL concentrations in plasma from 45 HAL-treated Japanese psychiatric patients in an attempt to look into possible ethnic differences. To our knowledge, this is the first report on the ratio of RHAL/ HAL in Japanese patients. We found a nonnormal, possibly bimodal, distribution of the RHAL/ HAL ratio, which has not been recognized in any populaticn before. Although our observation was done in a small group, the findings are suggestive of heterogeneity that may exist in the pharmacokinetics of haloperidol.

Methods Forty-five patients receiving HAL participated in this study. Most of them were hospitalized at the Shiga University Hospital and two affiliated mental hospitals for the treatment of their psychiatric illness. Six of them were seen and treated at the outpatient clinic. Patients who were on other neuroleptics or barbiturates were excluded. Antiparkinson drugs in doses as low as sufficient for control of adverse effects of HAL were allowed as needed. Biperiden, 2-l I mg/day, was given to 36 patients, and trihexyphenidyl, 3-6 mg/day, to 6 patients. Benzodiazepines as sleep inducers were prescribed in cases where patients complained of sleep difficulties. The doses were l-4 mg of flunitrazepam given to 22 patients. 0.25-0.5 mg of triazolam to 2 patients, 2-4 mg of flutoprazepam to 3 patients, l-2 mg of thienodiazepine to 3 patients, and IO mg of nitrazepam, 15 mg of tlurazepam, 6 mg of diazepam, and I2 mg of cloxazolam to each of 4 patients. That is, modest doses of benzodiazepines were given to 34 of 45 patients studied. For eight patients who complained of constipation, small doses of laxatives were given. Demographic data, medical histories, and laboratory data including hematology, serology, electrolytes, and urinalysis were collected for each patient, and patients with physical illness were excluded. The 45 patients consisted of 20 males and 25 females, and their ages ranged from I6 to 72 (mean = 36. I, SD = 13.7) years. Diagnoses were made using DSM-I11 criteria (American Psychiatric Association, 1980). Patients had schizophrenia (n = 26). schizophreniform disorder (n = 3), paranoid disorder (n = 2), atypical psychosis (n = IO), bipolar disorder (n = I), major depression (n = I). personality disorder (n = I), and developmenlal disorder (n = I). Onset of the illness ranged from age 5 to 70 (mean = 28. I, SD = 13.0) years. The body weights were in the range of 38-76 kg, and daily doses were titrated in the range of 2.25-80 (mean = 16.9, SD = 13.5) mg, or 0.048-1.270 (mean = 0.320, SD = 0.258) mg per kg body weight. HAL was given orally t.i.d. and maintained for at least 2 weeks at the same dosage until the time of blood sampling. Additional samples were obtained from 20 patients after 2-4 weeks. Blood (IO ml) was collected at 6 a.m., I2 hours after the evening dose, into heparinized vacutainers and centrifuged at 1000~. Aliquots of plasma were frozen at -80 “C until assayed. Plasma was extracted according to a modified procedure described by Fekete et al. (1981). In polypropylene tubes containing 2 ml of plasma, 25 ng of imipramine as internal standard and 0.3 ml of 0.7 A4 bicarbonate buffer, pH 9.7. were added, mixed well, and then extracted with 4 ml of heptane with 3Yo isoamyl alcohol by vigorous shaking for I5 min. The mixture was centrifuged at 1000x for 5 min, kept in a -20 “C freezer for 30 min, and then the organic layer was decanted into a polypropylene tube containing 0.2 ml of O.OSr/, orthophosphoric acid. vortexed for 30 sec. centrifuged at IOOOg for IO min. and the organic layer aspirated. Fifty PI of the aqueous layer was injected into the chromatograph. In the case of samples from patients on the low doses of 2.25-5 mgjday, 3 ml of plasma were extracted. The high performance liquid chromatography (HPLC) system consisted of a Waters 600E pump. a M712 auto sample processor, a 484 absorbance detector, and a M74l data module

113

equipped with a CSC spherisorb 5 I.rrn nitrile column, I5 X 0.46 cm i.d. The mobile phase was 40 mM phosphate buffer,pH 6.8, and acetonitrile, M/45 (Korpi et al., 1983). The UV detector was set at 210 nm. The minimum detectable amounts of both HAL and RHAL were as low as 0.5 ng/ml. The intra-assay coefficients of variation (c.v.‘s) for HAL and RHAL were 5.1% and 4.790, respectively, and interassay c.v.‘s were 5.9% for both compounds. The recoveries for HAL and RHAL were 92.5% and 85.490, respectively. Pearson’s product-moment analysis, regression analysis, and Student’s t test (two-tailed) were used, as well as probit plots for the analysis of skewed distributions.

Results Fig. 1A shows the relationship between daily dose per body weight (mg/ kg BW) and plasma concentrations of HAL. Although the plasma concentration of HAL ranged over three- to four-fold, it was linearly related to the dose (r = 0.92, p < 0.00 l), with an equation of: HAL (ng/ml) = 41.8 X DOSE (mg/ kg BW) - 1.24. Plasma concentrations of RHAL also appeared to be related to the dose (Fig. I B). Although there was a significantly positive correlation for the entire set of data (r = 0.82, p < O.OOl), concentrations of RHAL were somewhat differently distributed from those of HAL. High RHAL levels were found at high doses of HAL, with a dominant group identified in the lower part of the graph, while a small group of individuals with disproportionately high RHAL levels scattered in the upper part. The RHAL data did not appear to fit well to a linear regression line. Table 1 shows intraindividual variability of RHAL/ HAL ratios of 20 patients whose blood samples were taken twice and analyzed. The C.V. was 10.6%, and the

Fig. 1A. Relationship between daily dose (mglkg body weight) and level of haloperidol (HAL) in plasma (ng/ml)

0.5

I.0

DOSE OF HAL (mg/kgBW)

The equation of the relationshrp is: HAL (ngiml) = 41.8 X DOSE (mgikg SW) - 1.24 (r = 0.92, p < 0.001).

Fig. 1B. Relationship between dose (mg/kg body weight) plasma level of RHAL (ng/ml)

0.5

daily and

1.0

DOSE OF HAL (mg/kgElW)

The relationshrp between daily dose and plasma level of reduced haloperidol (RHAL) appears to be nonlinear. The line drawn is a linear regression lrne obtained from the data of 37 indivrduals with RHALiHAL ratios < 0.7 (closed circles). Closed squares indicate patrents with RHALIHAL ratros > 0.7 that appear to form another group.

114

Table 1. lntraindividual variability of reduced haloperidol/haloperidol (RHAUHAL) ratios RHAUHAL ratio Patient No.

Age

Sex

1st (a)

1

45

M

0.64

2

19

M

0.41

3

36

M

2nd (b)

(25)’

0.68

( 6) 0.33 ( 6)

0.43

4

19

F

0.54

5

24

F

0.50

6

42

7

30

8

64

(18)

a+b

(25)’

3.0%

( 6) 0.28 ( 6)

8.2%

0.61 0.32

F

( 3) 0.33 ( 7.5)

M

0.46

0.44

F

0.29

(18)

a-b

2.4% 6.1 %2

(24)

( 3) 0.57 ( 7.5)

22.0% 26.7% 2.2%

(18)

15.9%

9

38

F

( 4) 0.27 ( 2.25)

10

36

M

0.71

(30)

0.85

(20)

9.0%2

11

53

M

0.59

(20)

0.51

(20)

7.3%

12

45

F

1.32

(34)

1.28

(34)

1.5%

13

52

F

0.99

(40)

0.78

(40)

11.9%

14

37

M

0.26

(18)

0.35

(18)

14.8%

15

38

M

0.27

(25)

0.39

(25)

18.2%

16

22

F

0.43

(20)

0.46

(30)

17

52

F

0.34

(15)

0.43

(15)

11.7%

18

31

M

0.53

( 6)

0.38

(12)

l6.5%2

19

24

M

0.68

(18)

0.57

(18)

8.8%

20

35

M

1.22

(18)

1.69

(45)

1 6.22

Mean

5

0.40

( 4) 0.24 ( 2.25)

5.9%

3.4%2

SD

10.6 f 7.1%

I. Doses (mg/day) of HAL when blood samples were collected are shown in parentheses

2. Patients on different doses of HAL for the first and the second measurements.

ratios

between

the first and the second

samples were highly correlated (r = 0.90, on different doses of HAL also had small variation of RHAL/HAL ratios with a C.V. of 10.2% (SD = 5.370). RHAL/HAL ratios in the 45 patients ranged from 0. I5 to 2.08 (mean = 0.57, SD = 0.38). The lower part of Fig. 2 shows a frequency histogram of RHAL/ HAL ratios with a skewed distribution. The distribution of RHAL/ HAL ratios within a range of 0.1 to 0.7 appeared to have a normal distribution pattern, and another mode for a group of higher ratios was recognized. When the data were transformed into a probit plot (upper part of Fig. 2), the distribution was apparently nonlinear, with a break at 0.7. If the RHAL/HAL ratios were normally distributed, the probit plot would be totally linear, and therefore the distribution of RHAL/HAL ratios can be regarded as bimodal. The high RHAL/HAL ratio group in Fig. 2 consisted of eight subjects (18%) with RHAL/ HAL ratios of more than 0.7 (shown by solid squares in Fig. I B). There was also a significantly positive correlation between RHAL/HAL ratios and the daily doses per body weight (Fig. 3). The correlation coefficient in this case (r = 0.533, p < 0.01) was, however, lower than that of HAL or RHAL vs. the daily dose. In cases where patients were treated with different doses of HAL, the RHAL/ HAL ratios remained rather constant or specific to each individual (Table I).

p < 0.001).Five of these 20 individuals

115 The RHAL/ HAL ratio otherwise showed no significant or other clinical data such as period of HAL treatment, years after onset.

correlations with age, sex, age at onset of illness, or

Fig. 2. Cumulative frequency distribution (probit plot) and frequency histogram of plasma reduced haloperidol/haloperidol (RHALIHAL) ratios in 45 Japanese psychiatric patients

RHAL/HAL

Discussion Several previous studies indicated that plasma levels of HAL vary greatly among individuals. The highest level could be 5 times the lowest level, even when the patients were administered the same dose per body weight (Forsman et al., 1974; ltoh et al., 1980). A highly significant positive correlation between dose and plasma level of HAL has been shown in numerous studies (Forsman et al., 1974; Ericksen et al., 1978; Calil et al., 1979; Penny et al., 1979; Bjorndal et al., 1980; ltoh et al., 1980; Yoshimoto et al., 1980; Dunlop et al., 1982; Hollister and Kim, 1982; Moulin et al., 1982). Our data agreed with the previous findings, but showed even higher correlation coefficients. A possible reason for this could be that our plasma samples were collected from subjects whose compliance was reliably good. Penny et al. (1979) reported that the relationship between steady-state HAL concentrations in plasma and the dose in 22 subjects was expressed with an equation of HAL (ng/ml) = 0.48 X DOSE (mg) + 0.86. Other authors presented similar equations (Forsman et al., 1974; Itoh et al., 1980; Yoshimoto et al., 1980; Moulin et al., 1982)

116 Fig 3. Relationship between daily dose (mg/kg body weight) and plasma reduced haloperidol/haloperidol (RHAL/HAL) ratios

04

0

DOSE The equation of the linear regression p < 0.01).

1

.5

OF

line IS: RHALiHAL

HAL

1.5

(mg/kgBW)

ratio = 0.824 X DOSE (mgikg BW) + 0.318 (r = 0.533,

and, given a 50 kg BW subject administered IO mg HAL daily, HAL concentrations in plasma are expected to be 5.7, 7.3,5.9,6.8, and 29.9 ng/ml respectively, according to these equations. From our data, the patient’s steady-state plasma level was calculated to be 7.1 ng/ ml, in agreement with all previous data except those of Itoh et al. (1980) in which their radioimmunoassay method could not possibly discriminate RHAL from HAL (Korpi et al., 1984). The present data are in agreement with those on Japanese patients (Yoshimoto et al., 1980) for HAL levels in plasma vs. dose (mg/ kg BW), and when compared with three previous reports on Caucasians (Forsman et al., 1974; Penny et al., 1979; Moulin et al., 1982) no consistent difference was found. We could not confirm the previous data by Potkin et al. (1984) that Orientals showed 52% higher levels than Caucasians when their daily dose of HAL was maintained equally on 0.4 mg/ kg BW. The presence of RHAL as a metabolite of HAL was first described by Forsman and Larsson (1978). The formation of RHAL by human liver cytosol was demonstrated, and the enzyme catalyzing the reduction was shown to be a ketone reductase (Inaba and Kovacs, in press). Ereshefsky et al. (1984) reported that RHAL was about IO-25% as active as HAL in animals and humans, suggesting a possible role as a dopaminergic partial agonist. However, it was reported that RHAL was converted back to HAL in a rat model, and that it was found to have l/400 affinity to dopamine receptors as compared to HAL itself (Korpi and Wyatt, 1984; Chang et al., 1987b). In our studies, RHAL displaced ‘H-spiperone binding (0.2 nM 3Hspiperone, 50 mM TEAN buffer, IOOpCIMbutaclamol baseline, calf caudate) with an ICSo of 1600 nM, and under the same conditions, the IC,,, for HAL was I7 nM(Tang and Cheung, unpublished).

117 Although the data bases of all previous reports were small, there seemed to be an interethnic difference (RHAL/ HAL ratios appeared to be lower in Orientals than Caucasians). The mean value of the ratio was reported to be more than 1.0 in Caucasians (Ereshefsky et al., 1984; Korpi and Wyatt, 1984; Jann et al., 1986; Altamura et al., 1988), while Chang et al. (1987~) reported a mean value of 0.3 1 (SD 0.24) in 21 Chinese patients. Our results provided intermediate values, rather on the side of low RHAL/HAL ratios in Orientals. One possible explanation for this interethnic difference is that of pharmacogenetics. Previous studies did not focus on the mode of distribution of RHAL/HAL ratios in the populations investigated, probably because of their limited number of subjects, although Midha et al. (1989) reported on the intersubject variation in the pharmacokinetics of HAL and RHAL. We recognized that RHAL/HAL ratios in Japanese patients had a nonlinear, possibly bimodal, distribution pattern and found 18% of the patients to possess high RHAL/ HAL ratios. When we applied the same antimode (the ratio 0.7) to the data on Caucasians (Ereshefsky et al., 1984) there were four out of five (80%) individuals with high ratios (range of the ratio: 1.41-4.68). The data reported by Altamura et al. (1988) agreed with this distribution in that there were 83% (15 out of 18) individuals with high ratios (0.8 f-8.0) and I7yo individuals with low ratios (0.47-0.68). Thus, the majority of Caucasians (80-83%) exhibited a high RHAL/ HAL ratio, whereas most Orientals (82%) had a low ratio. However, there are several factors to be controlled, and caution is needed in pursuing these comparisons. For example, both groups of Japanese and Caucasian patients need to be compared in the same study before the existence of a unique metabolic polymorphism can be claimed, and this is, of course, the main purpose of our collaborative study in progress. Besides possible metabolic predisposition, some other factors influencing plasma RHAL/ HAL ratios should be taken into consideration: 1. Antiparkinson drugs and benzodiazepines given to the subject may have some effect of inducing microsomal drug enzymes which can enhance the metabolism of antipsychotics. Doses given to the patients were very small, usually less than 11 mg of antiparkinson drugs and less than 15 mg of benzodiazepines, as compared to barbiturates or anticonvulsants which are known to induce microsomal oxidative enzymes at higher daily doses. Previous administration of antipsychotics may alter HAL metabolism; however, most of the subjects studied were selected from those on HAL as the first choice. 2. The ages of patients may influence the RHAL/ HAL results. A reduction in the hepatic and renal blood flow in geriatric patients and consequent decreases in rates of first-pass effect of the liver as well as a slower rate of clearance may affect plasma HAL concentrations, altering RHAL/ HAL ratios. Of these 45 subjects, there were three individuals over the age of 60. RHAL/ HAL ratios in these three patients did not have any divergent values (Table 2A). Heterogeneity of the diagnostic groups also does not seem to be a factor affecting our interpretation of the results. Four individuals with diagnoses other than DSM-III psychotic disorders had values in accord with those of other individuals (Table 2B). 3. The very wide range of doses (2.2580 mg) and unequal distribution of subjects on different doses should be an important concern if one emphasizes the

Table 2. Plasma haloperidol (HAL) steady-state concentrations and reduced haloperidol/haloperidol (RHALIHAL) ratios in the aged (> age 60) subjects and those without DSM-III psychotic disorders DSM-III diagnosis

HAL dose per body weight (mg/kg BW)

64 F

295.92

0.074

1 .a5

0.347

72 F

298.90

0.132

3.3

0.424

63 F

298.30

0.195

5.4

0.593

0.545

Patients (Age, Sex)

Plasma HAL concentration (ng/ml)

RHALIHAL ratios

A. The aged patients

6. Patients without psychotic disorders 16 M

301 .a9

0.048

1.1

27 F

315.90

0.191

a.3

0.253

20 F

296.42

0.092

5.7

0.298

48 F

296.24

0.228

9.6

0.406

Mean + SD

0.303 f 0.234

11.4 + 0.6

0.57 f 0.38

(Range)

(0.048-l .270)

(1.1-55.2)

(0.15-2.08)

Total (n = 45)

nonlinearities in the metabolism of haloperidol. This may be indicated in the statistically significant, but not very high correlation (r = 0.553, Fig. 3) between the dose and RHAL/ HAL ratios. Alternatively, however, it is more likely that plasma concentrations of HAL and RHAL may be affected in a complex manner by differences and interindividual variabilities in affinities of two enzymatic reactions, HAL reduction and oxidative N-dealkylation of the central chain. The eight subjects with high RHAL/HAL ratios (>0.7) actually received higher doses of HAL than the remaining subjects with low RHAL/HAL ratios (Fig. 3). In the subjects on the higher doses of HAL, HAL may be metabolized faster, resulting in more RHAL. 4. Another concern about the data analysis is whether the cutoff point of 0.7 is appropriate; this value is derived from graphical estimation in Fig. 2, on the basis of the 45 patients studied. Our data are suggestive of the existence of a polymorphism

Table 3. Comparison between high and low reduced haloperidol/haloperidol @HAL/HAL) ratio groups (mean f SD)

Grouping

Number of subjects

Age (years)

Dose/body Plasma HAL weight concentration (mg/kg/day) (ng/ml)

8 (M:4; F:4)

40+

0.586 f 0.289

24.9 + 14.3

1.25 + 0.38

0.239 + 0.161

8.4 f 6.4

0.42 f 0.12

RHAUHAL ratios

A. High ratio group RHALiHAL > 0.7 B. Low ratio group RHALiHAL < 0.7

37 (M:l7, F:21)

10

35 f 13.8

(two-tailed Student’s tJ t

0.95

5.59

6.02

10.68

0

NS

< 0.001

< 0.001

< 0.001

119 in HAL metabolism. To confirm this preliminary observation, more extensive studies should be made to identify the location of the antimode. Such studies are now underway in our laboratories. Acknowledgment. manuscript.

We thank

Ms. Agnes

Bleiwas and Mary

Krasilowez

for reading

the

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