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Comparison of haloperidol and reduced haloperidol plasma levels in four different ethnic populations
0278
- 5846/92
@ 1992 Pmgaman
$15.00 press plc
CO~~SUN OF HALOPERIDUL AND REDUCED RALOPEi3IDOL PLASMALEVELS IN FOUR DIFFERENT EZHNIC POPULATIONS*
w* YAWN, ’ WEN-HOCNANG,2'3 Y.W. ‘FNANaS K.AN,4*4NAI G. EWOz2 HSXN-NAN HORNG CXEN,’TKNG Y. CNNN,’SHIN-KU IsXN,~CBING-PIAO CNIXQ CHESTER M. DAVIS,’ LARRY 9fXtESHEFSKY,4*E STEPlBX K. SAiCLhD,4+5ANN L. RICHARDS, * and WILLlX4 M. fX%JJLTEIS
BflExjm
&IN,
'Xe~~e~~~~vex3i~y, Atlanta, GA., USA, %iipek C&y Psyhiatrfc cSnt%r, Taipei, Taiwan, %ational Taiwan University, Taipei, Taiwan, C~llega of Phamaq, The 'fTniversity of Texas at Austin, Awtin, TX., USA, %he university of Texas Realtb Scfsnce Center at San Antonio, San Antonio, TX,, USA, dwilitary Psychiatric Center, Taipei, Taiwan, 7The University of Texas Health science Center at Houston, TX., USA, 'San Antonio State Hospital, San Antonio, TX., U.S.A, 9Kermille State Hospital, Kerrville, TX., USA. (Final form, July 1991) Abstract Lam et al.: thing, Y.W. Francis WWl-HO Jam, MiCltMbL W.8 Comparison of Raloperidol and R8dUC@d Haloperfdok Plasma fi;eValS ia Neuto-Paychophasmacol. E Pour Different Ethnic Populatfons. Prog. BfOl, Psychiat. 1992, ld<2) : 193-202, 1. PlasiRa haloperidof and reduced haloperidol concentration vere measured in four etbnie populations. 2.
3.
Plasma maples were obtained under steady-state conditions and obtained lo-12 hours post bedtkm dose and prior to the morning dose.
Haloperidol radiobummoassay
and
reduced haloperidol plasma and liquid chromatography.
levels
were
assayad
by
4.
A wide interpatient variability between haloperidol concentration was observed for each ethnic group.
5.
The Chinese group differed
6.
A nonlinear refati.onship was observed betwean haloperidol ax%d reduoed Further, the ha;lcrperidol pfamaa levels in each ethnio grouprelationship of ha%operidol to reduced haloperidol plasma levels These results suggest that varioua differed for each ethnic group. ethnic groups could Uetabolim haloperidol and reduoed haloperidol differently.
Rev words:
from the other ethhic populations,
ethuicity, haloperidol,
Abbxeviationq:
dose aud plasllta
reduced haloparidol.
haloparidol (EL), reduced haloperidol side effects (EPS), as naeded (PFW).
(RH), extrapyramidal
Ethnicfty has been suggested to play a key role in the metabofisn of various psychotropk agents. The biologicaL basis for ethnic variability in drug metabolism could be related to the enzymes and genes that deter&m? the Diversity in the enzyBIe quantity, patt@rn of metabolism fKalow, 1982). lrtoleculestructure and b~ochen~ca~ modifiers of enzym activity can be 193
199
M.W.Jannetat
Possible ~OLUWSS of variation of which clinical observations cannot accurately assess (Kalvw, 1982)* In neuroleptic agents, investigators have reported that lower neUrVleptfC dosages are observed in Asian populations compared to Caucasian% (Lin and Finder, 1983). In a fixed doss study of haloperidol (EL) with age-matched groups fH=rs)p a 52% higher NL serum concentrativns was recorded among Chinese than Caucasian psychiatric patients (P&kin et al,, 1984). In a SingLe fixed dose study of KL given intramuscularly or orally, Caucasian% had lower serum HL and prolactin Concentrations Compared to American-born and Foreign-born Asians (Lin et al.,1988). A lvngitudinal evaluation of HL doses and serum Concentrations reported that Asians experienced a higher incidence of EPS and s%rUm concentrations campared to Caucasians (Lin et al,, 1989). The pharmacokinetics of HZ in man has been extensively studied fForsnan and Ohan, 1996; HoUay et al., 1983: Cheng et al., 1987). HL metabplic prvfile involves the formation of piperridine and ~-f~uvroben~ylp~v~ivn~c acid metabolites [Forsatanet al., 1977). RedUctivn Of the benzylic ketvne C=C group to C-OH forming the reduced m@taboLita -reduced haloperidvf (RH) has been suggested to be other major metabolic route (Frvemntinget al, 1989). Equal plasma cv~Csntra~ions of RH t0 HL in psychiatric patients have. been reported (Forsman and Larrsori,1978). Svme investigationshave wggasted that elevated RH Concentrations are associated with a diminished therapeutio response to HL that plays a significant role in antipsychotic activity WhiCh should not be neglected (Ereshefsky et al., 1984; Shostak et al., 1987; Altamura st al., 1988). The site of formation of RH is located in the hepatic microsomes (KOri et al, 1985). RN had approximately l/3 to X/5 the potency of XL in prvducing elevated homovanillic acids levels in rat prefkanta~ cortex and caudate (Chang RH bad an 95% lower binding affinity for the dvpamine D-2 et al., 1987a). receptor compared to HL but an equal affinity at the sigma opfattbreceptor (Bowen et al,, 1990). RH was reported to be l/5 as potent as EL in i~ibi~~~~ RH was apomorphine-induced stereotype in rats (BrOWing et al., 1902). reported tv be oxidized back to HL in man and thus HL metabolism fvlfOWs a reduction/oxidation cycle or interconversion process fJann et al., 1990). HL and RH plasma concentrations have been reported in various atinic FfXOUpS (Jann et al., 1989: Soraeyaet al., X990), Two different ratios (high and low) of RF~and EL were repvrted among Japanese patient% {Someya et al., 1990). In comparing Chinese tv non-Chinese groups , although HL plasma concentration% did not difer, PIiwas shown to be a 3 fold lower in Chinese patients (Jann et aLI, this study will further extend our investigation of pv%%ible ethnic 1989) , differences in HL and RN plasma concentration%.
Chinese psycfrhakricpatients fN=L56) wers hospitalized at the Taipei City Psychiatric Center, tiilitaryPsychiatric center and National Taiwan University Hospital. The remaining Caucasian (N537), ffispanic (N-51) and Black (N=23) patients were hospitalized at the San Antonio State Hospital. All Chinese and nvn-chines% patient% were diagnosed a% schixizophrenics according to American PsycM.atri.c Association DSM-III criteria (3.980). xedical histories and laboratory data (SEA U/60, urinalysis, hematology, serology and electrolyte%) were collected from each patient. All laboratory parameters were within normal Lim.i.ts.Schizophrenic patients wsre selected for comparative analysi% based upvn the following parameters: %table HL dosage for a minimum of seven days; no enzyme inducing agents (e.g. phenobarbital) or inhibiting drugs (e.g. cimetidine); nonsmokers or persons who smoked less than 1 pack per day of cigarette% (usually approximately J/2 pack): no oral or intramuscular HI, administered PRN 48 hours prior tv serUm sampling; and steady-%tate HL serum concentrations obtained at each dvsagca.
Haloperldolandreducedhaloperldolplasmalevels
195
The only concurrent medications allowed were benztropine and trihyphenidyl which do not influence haloperidol serum concentrations (Froemming, et al., 1989). Druus Janseen HL used in Taiwan and San Antonio were purchased fr0lIl Pharmaceuticals, Beerse, Belgium and McNeil Pharmaceuticals, Spring House, PA, USA, respectively.
Clinical assessments made by each clinician was without utilization of a standardized rating scale but based upon patient interviews, patient to patient interactions, unit staff and nursing information. The incidence of extrapyramidal side effects could not be accurately determined due to the prophylactic use of anticholinergic medications in some patients. Therefore, comparative analysis was not attempted for clinical response and adverse effects. Both non-Chinese and Chinese patients' HL dosages were individually titrated based upon their clinical response. HL and RH blood samples were obtained lo-12 hours post evening dose and prior to the morning dose. Samples in non-Chinese ethnic groups were centrifuged and plasma specimens were sent to the University of Texas Mental Science Institute (UTMSI) for analysis. Chinese blood samples were centrifuged and plasma stored at -60 C until assay. Reduced haloperidol and haloperidol assayed by UTMSI utilized a combined liquid chromatography and radioimmunoassay and interassay coefficients of variation less than 10% for reduced haloperidol and haloperidol at 5-10 ng/ml (Browning et al., 1985). Chinese plasma haloperidol and reduced haloperidol samples were assayed via reverse phase liquid chromatography (LC) with electrochemical detection (Korpi et al., 1983). The minimum level of sensitivity was 0.4 ng/ml with an intrassay and interassay coefficients of variation from 4% to 12% at 2-10 ng/ml. The UTMSI set up the identical LC technique used in Chinese patients and compared identical patient samples with LC and LC/RIA assay methods in which the correlation coefficients for ML and RH were r=0.96 (p
M. W. Jam et al.
f96
a %
Haloperidol and reduced haloperldol plasma levels
-_I---
-----CHINESE
(N- 156f
---HISPANIC
(N* 51)
--CAUCASIAN -BLACK
_t______~-___..
-__
A
(N= 37) (N= 231
.- .-
l..______._i--__-.._L-__~
0
10
20
197
..__-
30
40
_,’ **
.’
.- *‘
i__._-__-j_---l~
L-_.-_^-L_
60
50
70
80
90
DOSE mg/day 180
_-
I------ - - - -HlSPAN[C -BLACK
,40
CAUCAStAN
_ --
{N= 51)
B
(N* 23)
130
- ~~~~~~~GiINESE
120
-
i
.’
/ 1’
(N= 371 (N= 156)
110ioo-
..__-L_._-L_ -J.--d---__" 0
10
20
30
40
Haloperidol fig
1%
&Relationship
60
Plasma Level
70
-..--.%_I 60
90
(ng/rnl)
between HL daily dose (mg/day) and plasma various ethnic populations. 8. Relationship HI, and RH plasma levels for different ethnic grOupsB
concentrations between
L.____L..____I_ 60
forth
198
M. W.Jann elal.
The relationship between HL and FUiplasma levels (ng/ml) for the different ethnic groups are shown in Fig. 1B. Upon inspection of the graphic plots for the different ethnic populations, a non-linear relationship appears between FUiand HL plasma concentrations. Figure 1B demonstrates distinct differences between each ethnic group regarding HL and FUiplasma level relationships. The correlation coefficient values for each group are: Chinese rx0.592, d.f.=1,151, F=223.449; Black r2=0.762 d.f.=l,Zl, F-67.561; Caucasian r2=0.748, d.f.=1,35, Fs103.887: and Hispanic r'=0.611, d.f.=1,53, ~~72.125. All of the corresponding p values were
Haloperidoland reducedhaloperidolplaama levels
199
analysis proposes that the most significant factors The regression influencing I-ILplasma concentrations were HL dose and N-I plasma levels. Ethnicity was only a significant factor for the Chinese and Black group. The Black group had only a p=O.Q546, but based upon the various data from the dose to haloperidol plasma levels had reduced haloperidol to haloperidol plasma concentration relationships, this ethnic group most likely can be a significant factor influencing haloperidol plasma levels. Age and weight were not significant factors. However, these ethnic populations did not have any geriatric (>65 years) patient in this data set. Therefore, age could not be a significant factor between in patients < 65 years old. Weight also seemed not to be a significant contributor and other researchers have reported this finding (Forsman and Ohman, 1977; Jann et al., 1985). The relationship between EH and HL plasma concentrations in Fig. 18 appeared to be nonlinear. Previous investigations have also documented a potential nonlinear relationship between I-ILand BH concentrations (Browning et al., 1985). When HL plasma levels are less than long/ml, no significant differences were apparent among the different ethnic populations. In general, the Black group had the highest elevation of EH plasma levels. The Hispanic group resembled the Black group but the curve was shifted to the right. The Chinese group had lower BH but higher HL plasma concentration as indicated by the curve shifted to the right. However, the IUi plasma levels are disproportional higher when HL plasma concentrations have been previously reported in Chinese patients with haloperidol plasma levels less than 20ng/ml (Chang et a:., 1987b). The results from Fig. 1B suggests that the various ethnic groups can converted HL to EH at different metabolic rates. The enzyme system catalyzing this conversion is HL reductase (Inaba and Kovacs, 1989) which might differ among different individuals. In Chinese patients, EH can also be oxidized back to HL, but this reaction appears to be less prominent than reduction of HL (Jann, et al., 1990). This interconversion (reduction/oxidation cycle) process has been noted for other ethnic populations (Charkraborty, et al., The 1989) and could be a major source for interpatient variability. disproportional increase in BH plasma concentrations also seen in these ethnic groups in Pig. lB,would suggest the possibility of a saturation process at either the interconversion step or directly from EH metabolism. In the guinea pig model, RH was also reported to be glucuronidated to Eliglucuronide and shown to undergo biliary recycling and convert back to Eli (Eddington and Young, 1989). The UDP-glucuronyl transferase enzyme system regulates the glucuronide metabolic pathway (Burchell, et al., 1990). DifferenCes in this enzyme complex might also exist in different individuals. Therefore, two major sources can contribute towards the disproportional
increase in plasma concentrations of RH. The limitations of this study are quite evident. Data gathered from two different countries over different time periods are subject to potential errors. Differences in prescribing patterns preclude a fixed-dose study design. The sample size for the non-Chinese groups; Caucasian, Hispanic and Black populations did not equal the Chinese population. However, gathering that quantity of patients for each group could take many years. The assay methodologies differed but the correlations between he LC and RIA for reduced haloperidol and haloperidol were almost equivalent. Oxidation of reduced haloperidol conversion back to haloperidol has not yet been quantified in nonChinese patients. Clinical assessments for response and adverse effects were not evaluated. Conclusions This report supports that HL and RH plasma concentrations differs among various ethnic populations. This report also supports previous observations reported by different investigators in a smaller number of psychiatric patients.
200
M.W.Jann etd. Acknowledaements
Supported bY grant NSC 79-412-B109-01 from the National Science Council and Taipei City Government, Taiwan, Republic of China. References A., and ALTAMURA, C.A., MAURI, M., CAVALLARO, R., COIACURIO, F., GORNI, BAREGGI, S.(1988) Reduced haloperidol/haloperidol ratio clinical outcome in schizophrenia: preliminary evidences. Prog Neuropsychopharmacol Biol Psychiatr 12: 689-694. AMERICAN PSYCHIATRIC ASSOCIATION. (1980) DSM-III: Diagnostic and Statistical D.C., APA. manual of mental disorders. 3rd edition, Washington, BOWEN, W.D., MOSES, E.L., TOLENTINO, P.J., and WALKER, J.M. (1990). Metabolites of haloperidol display preferential activity at sigma opiate receptors compared to dopamine D-2 receptors. Eur J Pharmacol m:lll118. BROWNING, J.L., SILVERMAN, P.B., HARRINGTON, C.A. and DAVIS, C.M.*(1982) Preliminary behavioral and pharmacologic studies on the haloperidol metabolite reduced haloperidol. Sot Neurosci Abs 8: 470. (1985) Quantification of BROWNING, J.L., HARRINGTON, C.A. and DAVIS, C.M. reduced haloperidol and haloperidol by radioimmunoassay. J Immunoassay 6: 45-66. BURCHELL, B., COUGHTRIE, M.W.H, and WADDEL, L. (1990) Expression and regulation of UDP-glucuronosyl-transferases. Proceedings VIIth international Symposium on Microsomes and Drug Oxidations, Karolinska Institute, Stockholm, Sweden, abs. p.29. J.K., CHAKRABORTY, B.S., HUBBARD, J.W., HAWES, E.W., MCKAY, G., COOPER, K.K. (1989) Interconversion GURNSEY, T., KORCHINSKI, E.D, and MIDHA, between haloperidol and reduced haloperidol in healthy Volunteers. Eur J Clin Pharmacol 37: 45-48. CHANG, W.H., CHEN, T.Y, and YEH, E.K. (1987a Time-response curves of hemoy vanillic acid in caudate and prefrontal cortex following acute neuroleptlc administration. Psychopharmacology 93: 403-404. CHANG, W.H., CHEN, T.Y., LEE, C.F ., HU, W.H, and YEH, E.K. (1987b) Low plasma reduced haloperidol/haloperidol ratios in Chinese patients. Biol Psychiatr 22: 1406-1408. CHENG, Y.F., PAALZOW, L.K., BONDESSON, U., EKBLQOM, B., ERIKSSON K,ERIKSSON, S.O., LINDBERG, A, and LINSTROM, L. (1987) Pharmacokinetics of haloperidol in psychotic patients. Psychopharmacy 91: 410-414. EDDINGTON N.D, and YOUNG, D.L. (1989) Biliary excretion of reduced haloperidol glucuronide. Psychopharmacology a: 410-414. ERESHEFSKY, L., DAVIS, C.M., HARRINGTON, C.A., JANN, M.W., BROWNING J L SAKLAD, S.R, and BURCH, N.R. (1984) Haloperidol and reduced halApe& plasma levels in selected schizophrenic patients. J Clin Psychopharmacol 4: 138-142. FORSMAN, A., and OHMAN, R. (1976) Pharmacokinetic studies of haloperidol in man. Curr Ther Res a: 319-336. FORSMAN, A., and OHMAN, R. (1977) Applied pharmacokinetics of haloperidol in man. Curr Ther Res 21: 396-410. FORSMAN, A., FOLSCH, G., LARSSON, M., and OBMAN, R. (1977) On the metaboligm haloperidol in man. Curr Ther Res 21: 606-617.
and DAVIS, C.M. (1989) PharmacoFROENNING, J.H., LAM, Y.W.F., JANN, M.W., kinetics of haloperidol. Clin Pharmacokinet U: 396-423. HOLLEY, F.O., NAGLIoZEI, J.R., STANSXI, D-R., LOMBROEO, L, and HOLLISTER, L.E. (1983) Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol Ther 51: 477-484. INABA, T, and KOVACS, J. (1989) Haloperidol reductase in human and guinea Pigs livers. Drug Metab Dispos a: 330-333. JANN, M.W., LUDDEN, T.M., ERXSREFSKY, L, and SAXLAD, S,R. (1985) Preliminary analysis of haloperidol population kinetics in schizophrenics. Clin schizophrenics. Clin Pharmacol Ther z: 203. JAKN, M.W., CHANG, W.H., DAVIS, C.M,, CREN, T-Y., LUNG, F.W., ERESREFSXY, L., (1989) Haloperidol and reduced haloperidol SAXLAD, S.R., and RICHARDS, A.L. plasma levels in Chinese end non-Chinese psychiatric patients. Psychiatr Ree 2p: 45-52. H.W., MM, Y.W.F., and CMANG, W,H. (1990) Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients. schizophrenic patients. Psychopharmacology U: 107-111.
JANN,
XALOW, W, (1982) Ethnic differences in drug metabolisxn. Clin Pharmacokinet 2:373-400. XIRCH, D.G., BIGELOW, L.B., and WYATT, R,J.(1985) The interpretation of plasma haloperidol concentrations. Arch Gen Psychiatr aa: 838-839. XORPI, E.R., PHELPS, B.H., GRANGER, Ii., CHAHG, W.H., CHOIR, M., WEEK, J.L., and WYATT, R.J. (1983) Simultaneous determinations of haloperidol and its reduced metabolite in serum and plasma by isocratic liquid chromatography with electrochemical detection. Clin Chem a: 624- 629. XORPI, E.R., COSTAXOS, D.T., and WYATT, R.J. (1985) Rapid formation of reduced haloperidol in guinea pigs following haloperidol administration Acta Pharmacol Toxic01 z: 94-98. LIN, K.&f., and FINDER, E. Psychiatr m: 490-491.
(1983) Neuroleptic dooage for Asians.
Am J
LIN, R.N., POLA?JD, R.E., LAUr J.K., and RU3IN, R.T. (1988) Haloperidol and prolactic concentrations in Asians and Caucasians. J Clin Psychopharmaool 8: 195-201. POTKIN, S .G., SEEN, Y., PARDES, H., PBELPS, B.H., ZROU, D., .%iU,I,.,KORPI E.R., and WYATT, R-J. (1984) Waloperidol concentrations elevated in Chinese patients. Psychiatr Res &$: 167-172. SAS (1988) User's Guide: Statistics, varefon 5 edition. SAS Institute, Inc., Gary, N.C., PP (1987) SEOSTAK, R., PEREL, J.M., STILLER, R.L., WYMAN, W., and CIJRRAX,S. plasma haloperidol and clinical response: a role for reduced haloperidol in antipeychotic activity? J Clin Psychopharmacol Z: 394-400. I.&i., INAEA, T., CHEUNG, S.W., and SOMEYA, T., TAILAEASHI, S., sHn3~sK, plasma: TANG, Sew. (1990) Reduced halope~idol/haloperidol ratio8 in polymorp&ism in Japanese psychiatric patients. Psychiatr. Res. 31: Ill-I2G-
VOLAVXA, J., and COOPER, T,B (1987) Review of haloperidol blood levels and clinical response: looking through the window. J Clin Psychopharsuacol1: 25-30.
202
M.W.
Jam
et al.
Inquiries and reprint requests should be addressed to: Wen-Ho Chang, M.D. Chief, Laboratory of Biological Psychiatry Taipei City Psychiatric Center 309 Sung-Te Road Taipei, Taiwan 10510 Republic of China
- 5846/92
@ 1992 Pmgaman
$15.00 press plc
CO~~SUN OF HALOPERIDUL AND REDUCED RALOPEi3IDOL PLASMALEVELS IN FOUR DIFFERENT EZHNIC POPULATIONS*
w* YAWN, ’ WEN-HOCNANG,2'3 Y.W. ‘FNANaS K.AN,4*4NAI G. EWOz2 HSXN-NAN HORNG CXEN,’TKNG Y. CNNN,’SHIN-KU IsXN,~CBING-PIAO CNIXQ CHESTER M. DAVIS,’ LARRY 9fXtESHEFSKY,4*E STEPlBX K. SAiCLhD,4+5ANN L. RICHARDS, * and WILLlX4 M. fX%JJLTEIS
BflExjm
&IN,
'Xe~~e~~~~vex3i~y, Atlanta, GA., USA, %iipek C&y Psyhiatrfc cSnt%r, Taipei, Taiwan, %ational Taiwan University, Taipei, Taiwan, C~llega of Phamaq, The 'fTniversity of Texas at Austin, Awtin, TX., USA, %he university of Texas Realtb Scfsnce Center at San Antonio, San Antonio, TX,, USA, dwilitary Psychiatric Center, Taipei, Taiwan, 7The University of Texas Health science Center at Houston, TX., USA, 'San Antonio State Hospital, San Antonio, TX., U.S.A, 9Kermille State Hospital, Kerrville, TX., USA. (Final form, July 1991) Abstract Lam et al.: thing, Y.W. Francis WWl-HO Jam, MiCltMbL W.8 Comparison of Raloperidol and R8dUC@d Haloperfdok Plasma fi;eValS ia Neuto-Paychophasmacol. E Pour Different Ethnic Populatfons. Prog. BfOl, Psychiat. 1992, ld<2) : 193-202, 1. PlasiRa haloperidof and reduced haloperidol concentration vere measured in four etbnie populations. 2.
3.
Plasma maples were obtained under steady-state conditions and obtained lo-12 hours post bedtkm dose and prior to the morning dose.
Haloperidol radiobummoassay
and
reduced haloperidol plasma and liquid chromatography.
levels
were
assayad
by
4.
A wide interpatient variability between haloperidol concentration was observed for each ethnic group.
5.
The Chinese group differed
6.
A nonlinear refati.onship was observed betwean haloperidol ax%d reduoed Further, the ha;lcrperidol pfamaa levels in each ethnio grouprelationship of ha%operidol to reduced haloperidol plasma levels These results suggest that varioua differed for each ethnic group. ethnic groups could Uetabolim haloperidol and reduoed haloperidol differently.
Rev words:
from the other ethhic populations,
ethuicity, haloperidol,
Abbxeviationq:
dose aud plasllta
reduced haloparidol.
haloparidol (EL), reduced haloperidol side effects (EPS), as naeded (PFW).
(RH), extrapyramidal
Ethnicfty has been suggested to play a key role in the metabofisn of various psychotropk agents. The biologicaL basis for ethnic variability in drug metabolism could be related to the enzymes and genes that deter&m? the Diversity in the enzyBIe quantity, patt@rn of metabolism fKalow, 1982). lrtoleculestructure and b~ochen~ca~ modifiers of enzym activity can be 193
199
M.W.Jannetat
Possible ~OLUWSS of variation of which clinical observations cannot accurately assess (Kalvw, 1982)* In neuroleptic agents, investigators have reported that lower neUrVleptfC dosages are observed in Asian populations compared to Caucasian% (Lin and Finder, 1983). In a fixed doss study of haloperidol (EL) with age-matched groups fH=rs)p a 52% higher NL serum concentrativns was recorded among Chinese than Caucasian psychiatric patients (P&kin et al,, 1984). In a SingLe fixed dose study of KL given intramuscularly or orally, Caucasian% had lower serum HL and prolactin Concentrations Compared to American-born and Foreign-born Asians (Lin et al.,1988). A lvngitudinal evaluation of HL doses and serum Concentrations reported that Asians experienced a higher incidence of EPS and s%rUm concentrations campared to Caucasians (Lin et al,, 1989). The pharmacokinetics of HZ in man has been extensively studied fForsnan and Ohan, 1996; HoUay et al., 1983: Cheng et al., 1987). HL metabplic prvfile involves the formation of piperridine and ~-f~uvroben~ylp~v~ivn~c acid metabolites [Forsatanet al., 1977). RedUctivn Of the benzylic ketvne C=C group to C-OH forming the reduced m@taboLita -reduced haloperidvf (RH) has been suggested to be other major metabolic route (Frvemntinget al, 1989). Equal plasma cv~Csntra~ions of RH t0 HL in psychiatric patients have. been reported (Forsman and Larrsori,1978). Svme investigationshave wggasted that elevated RH Concentrations are associated with a diminished therapeutio response to HL that plays a significant role in antipsychotic activity WhiCh should not be neglected (Ereshefsky et al., 1984; Shostak et al., 1987; Altamura st al., 1988). The site of formation of RH is located in the hepatic microsomes (KOri et al, 1985). RN had approximately l/3 to X/5 the potency of XL in prvducing elevated homovanillic acids levels in rat prefkanta~ cortex and caudate (Chang RH bad an 95% lower binding affinity for the dvpamine D-2 et al., 1987a). receptor compared to HL but an equal affinity at the sigma opfattbreceptor (Bowen et al,, 1990). RH was reported to be l/5 as potent as EL in i~ibi~~~~ RH was apomorphine-induced stereotype in rats (BrOWing et al., 1902). reported tv be oxidized back to HL in man and thus HL metabolism fvlfOWs a reduction/oxidation cycle or interconversion process fJann et al., 1990). HL and RH plasma concentrations have been reported in various atinic FfXOUpS (Jann et al., 1989: Soraeyaet al., X990), Two different ratios (high and low) of RF~and EL were repvrted among Japanese patient% {Someya et al., 1990). In comparing Chinese tv non-Chinese groups , although HL plasma concentration% did not difer, PIiwas shown to be a 3 fold lower in Chinese patients (Jann et aLI, this study will further extend our investigation of pv%%ible ethnic 1989) , differences in HL and RN plasma concentration%.
Chinese psycfrhakricpatients fN=L56) wers hospitalized at the Taipei City Psychiatric Center, tiilitaryPsychiatric center and National Taiwan University Hospital. The remaining Caucasian (N537), ffispanic (N-51) and Black (N=23) patients were hospitalized at the San Antonio State Hospital. All Chinese and nvn-chines% patient% were diagnosed a% schixizophrenics according to American PsycM.atri.c Association DSM-III criteria (3.980). xedical histories and laboratory data (SEA U/60, urinalysis, hematology, serology and electrolyte%) were collected from each patient. All laboratory parameters were within normal Lim.i.ts.Schizophrenic patients wsre selected for comparative analysi% based upvn the following parameters: %table HL dosage for a minimum of seven days; no enzyme inducing agents (e.g. phenobarbital) or inhibiting drugs (e.g. cimetidine); nonsmokers or persons who smoked less than 1 pack per day of cigarette% (usually approximately J/2 pack): no oral or intramuscular HI, administered PRN 48 hours prior tv serUm sampling; and steady-%tate HL serum concentrations obtained at each dvsagca.
Haloperldolandreducedhaloperldolplasmalevels
195
The only concurrent medications allowed were benztropine and trihyphenidyl which do not influence haloperidol serum concentrations (Froemming, et al., 1989). Druus Janseen HL used in Taiwan and San Antonio were purchased fr0lIl Pharmaceuticals, Beerse, Belgium and McNeil Pharmaceuticals, Spring House, PA, USA, respectively.
Clinical assessments made by each clinician was without utilization of a standardized rating scale but based upon patient interviews, patient to patient interactions, unit staff and nursing information. The incidence of extrapyramidal side effects could not be accurately determined due to the prophylactic use of anticholinergic medications in some patients. Therefore, comparative analysis was not attempted for clinical response and adverse effects. Both non-Chinese and Chinese patients' HL dosages were individually titrated based upon their clinical response. HL and RH blood samples were obtained lo-12 hours post evening dose and prior to the morning dose. Samples in non-Chinese ethnic groups were centrifuged and plasma specimens were sent to the University of Texas Mental Science Institute (UTMSI) for analysis. Chinese blood samples were centrifuged and plasma stored at -60 C until assay. Reduced haloperidol and haloperidol assayed by UTMSI utilized a combined liquid chromatography and radioimmunoassay and interassay coefficients of variation less than 10% for reduced haloperidol and haloperidol at 5-10 ng/ml (Browning et al., 1985). Chinese plasma haloperidol and reduced haloperidol samples were assayed via reverse phase liquid chromatography (LC) with electrochemical detection (Korpi et al., 1983). The minimum level of sensitivity was 0.4 ng/ml with an intrassay and interassay coefficients of variation from 4% to 12% at 2-10 ng/ml. The UTMSI set up the identical LC technique used in Chinese patients and compared identical patient samples with LC and LC/RIA assay methods in which the correlation coefficients for ML and RH were r=0.96 (p
M. W. Jam et al.
f96
a %
Haloperidol and reduced haloperldol plasma levels
-_I---
-----CHINESE
(N- 156f
---HISPANIC
(N* 51)
--CAUCASIAN -BLACK
_t______~-___..
-__
A
(N= 37) (N= 231
.- .-
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20
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30
40
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.- *‘
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50
70
80
90
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CAUCAStAN
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Haloperidol fig
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&Relationship
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Plasma Level
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between HL daily dose (mg/day) and plasma various ethnic populations. 8. Relationship HI, and RH plasma levels for different ethnic grOupsB
concentrations between
L.____L..____I_ 60
forth
198
M. W.Jann elal.
The relationship between HL and FUiplasma levels (ng/ml) for the different ethnic groups are shown in Fig. 1B. Upon inspection of the graphic plots for the different ethnic populations, a non-linear relationship appears between FUiand HL plasma concentrations. Figure 1B demonstrates distinct differences between each ethnic group regarding HL and FUiplasma level relationships. The correlation coefficient values for each group are: Chinese rx0.592, d.f.=1,151, F=223.449; Black r2=0.762 d.f.=l,Zl, F-67.561; Caucasian r2=0.748, d.f.=1,35, Fs103.887: and Hispanic r'=0.611, d.f.=1,53, ~~72.125. All of the corresponding p values were
Haloperidoland reducedhaloperidolplaama levels
199
analysis proposes that the most significant factors The regression influencing I-ILplasma concentrations were HL dose and N-I plasma levels. Ethnicity was only a significant factor for the Chinese and Black group. The Black group had only a p=O.Q546, but based upon the various data from the dose to haloperidol plasma levels had reduced haloperidol to haloperidol plasma concentration relationships, this ethnic group most likely can be a significant factor influencing haloperidol plasma levels. Age and weight were not significant factors. However, these ethnic populations did not have any geriatric (>65 years) patient in this data set. Therefore, age could not be a significant factor between in patients < 65 years old. Weight also seemed not to be a significant contributor and other researchers have reported this finding (Forsman and Ohman, 1977; Jann et al., 1985). The relationship between EH and HL plasma concentrations in Fig. 18 appeared to be nonlinear. Previous investigations have also documented a potential nonlinear relationship between I-ILand BH concentrations (Browning et al., 1985). When HL plasma levels are less than long/ml, no significant differences were apparent among the different ethnic populations. In general, the Black group had the highest elevation of EH plasma levels. The Hispanic group resembled the Black group but the curve was shifted to the right. The Chinese group had lower BH but higher HL plasma concentration as indicated by the curve shifted to the right. However, the IUi plasma levels are disproportional higher when HL plasma concentrations have been previously reported in Chinese patients with haloperidol plasma levels less than 20ng/ml (Chang et a:., 1987b). The results from Fig. 1B suggests that the various ethnic groups can converted HL to EH at different metabolic rates. The enzyme system catalyzing this conversion is HL reductase (Inaba and Kovacs, 1989) which might differ among different individuals. In Chinese patients, EH can also be oxidized back to HL, but this reaction appears to be less prominent than reduction of HL (Jann, et al., 1990). This interconversion (reduction/oxidation cycle) process has been noted for other ethnic populations (Charkraborty, et al., The 1989) and could be a major source for interpatient variability. disproportional increase in BH plasma concentrations also seen in these ethnic groups in Pig. lB,would suggest the possibility of a saturation process at either the interconversion step or directly from EH metabolism. In the guinea pig model, RH was also reported to be glucuronidated to Eliglucuronide and shown to undergo biliary recycling and convert back to Eli (Eddington and Young, 1989). The UDP-glucuronyl transferase enzyme system regulates the glucuronide metabolic pathway (Burchell, et al., 1990). DifferenCes in this enzyme complex might also exist in different individuals. Therefore, two major sources can contribute towards the disproportional
increase in plasma concentrations of RH. The limitations of this study are quite evident. Data gathered from two different countries over different time periods are subject to potential errors. Differences in prescribing patterns preclude a fixed-dose study design. The sample size for the non-Chinese groups; Caucasian, Hispanic and Black populations did not equal the Chinese population. However, gathering that quantity of patients for each group could take many years. The assay methodologies differed but the correlations between he LC and RIA for reduced haloperidol and haloperidol were almost equivalent. Oxidation of reduced haloperidol conversion back to haloperidol has not yet been quantified in nonChinese patients. Clinical assessments for response and adverse effects were not evaluated. Conclusions This report supports that HL and RH plasma concentrations differs among various ethnic populations. This report also supports previous observations reported by different investigators in a smaller number of psychiatric patients.
200
M.W.Jann etd. Acknowledaements
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Inquiries and reprint requests should be addressed to: Wen-Ho Chang, M.D. Chief, Laboratory of Biological Psychiatry Taipei City Psychiatric Center 309 Sung-Te Road Taipei, Taiwan 10510 Republic of China