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Lack of pharmacokinetic interaction between buspirone and haloperidol in schizophrenic patients
37
P Poster Presentations flicting results on 3H_IMlbinding sites and aging, we investigated possible age-related changes in platelet 3H-Par binding. Twenty subjects bewteen 78 and 85 years of age and 20 young ones (bewteen 25 and 38 years og age) were included in the study. Human platelets and 3H-Par binding were carried out following Marazziti et al.'s method (1995). Statistical analysis was performed by means of the umpaired Student's test. There was no significant difference in 3H-Par binding parameters between elderly and young subjects, a finding that suggests that 3H-Par binding sites are not sensitive to aging, at variance with 3H-IMI binding sites.
IP-2-1 I Lack of Pharmacokinetic Interaction Between Buspirone and Haloperidol in Schizophrenic Patients
M.W. lann, H.F. Huang, T.P. Chang, 1.S. Chen, D.J. luang, S.K. Lin, Y.w.F. Lam, c.P. Chien, W.H. Chang. Mercer University, Taipei City Psychiatric Center and University of Texas at Austin Buspirone (B) is non-benzodiazepine anxiolytic agent that does not produce sedation and psychomotor impairment. Haloperidol (H) is a neuroleptic drug commonly used in the treatment of psychiatric disorders. These two drugs are likely to be co-administered in psychiatric patients. This study was conducted in two phases: I) an in-depth pharmacokinetic study (N '" 11) and 2) at steady-state condition (N '" 27). H was assay by the HPLC with EC detection. The lower limit of detection was 0.4 ng/ml with CV less than 10% at 2-20 ng.m\. H doses ranged from 10-40 mg/day and B doses 10 mg TID. HL plasma levels (Cps) were obtained over a 24 hour time period in phase I. During phase 2, H Cps were measured at baseline and weeks 2 and 6. No significant changes were found in the pharmacokinetic parameters of H during B co-administration in phase I. H clearance (CLIF) '" 0.85 Llhrlkg vs. H + B CLIF '" 0.82 Llhrlkg. During phase 2, steady-state mean H Cp's remained unchanged during the addition of B. Mean H Cps at baseline, weeks 2 and 6 were 12.7 mg/ml, 12.7 ng/ml, and 13.6 ng/ml, respectively. These results indicate that addition of B does not significantly alter H disposition.
I P-2-21
Effect of Rifampin on Plasma Concentrations and Clinical Responses of Haloperidol in Schizophrenics 1.1.Woo, Y.H. Kim, r.c. Shim, 1.G. Shin, S.G. Shin. Departments of Psychiatry & Pharmacology, Seoul Nat'l Univ. Hosp. & lnje Univ. Hosp, Seoul, Korea
We assessed the changes of plasma haloperidol (HAL) concentrations and clinical responses repeatedly up to 4 wks after coadministration or discontinuation of rifampin (RIP) in 12 schizophrenic patients taking HAL alone (group I) and 5 schizophrenic patients taking HAL with antituberculotic drugs (group II). After coadministration of RIP in the group I, daily through concentrations decreased to 63% of baseline level by day 3,41.3% by day 7 and 30% by day 28. Conversely, after discontinuation of RIF in the group II, plasma HAL concentrations increased to 140.7% of baseline level by day 3, 228.7% by day 7 and 329% by day 28. The change in the BPRS score by 30% or greater was considered as a positive clinical response due to drug interaction. Using this criterion, 50% of the patients responded according to the BPRS total score and 25% of those responded according to the score of BPRS subscale for psychiatric symptoms in the group I. No positive response was observed in the group II. These results strongly suggest that RIF interacts with plasma HAL concentrations and affects the clinical response of HAL, and careful monitoring should be considered in case of coadministration or discontinuation of RIF in schizophrenics taking HAL.
IP-2-3!
The Quantitative Analysis of a Haloperidol Derivative andIts Neurotoxic Metabolites in Baboons
K. Avent I, C. Van der Schyf ", D. Eyles 3, N. Castagnoli 2, S. Pond I. I Dept ofMedicine, Univ ofQueensland, Australia; 2 Dept ofChemistry, Virginia Polytechnic, USA; 3 Clinical Studies Unit, Walston Park Hospital, Australia Haloperidol (HP) is a commonly used neuroleptic drug which produces extrapyramidal syndromes such as tardive dyskinesia (TD)
and drug-induced parkinsonism. It has been reported previously that two pyridinium metabolites, 4-(4-chlorophenyl)-I-(4-fluorophenyl)-4oxobutyl-pyridinium (HPJ>'") and 4-(4-chlorophenyl)-I-(4-fluorophenyl)4-hydroxybutyl-pyridinium (RHPP+), which are similar in structure to the well characterized parkinsonian agent l-methyl-4-phenyl pyridinium (MPP+), are found in the urine and blood of patients treated with HP [I]. This metabolism is presumed to occur via 4-(4-chlorophenyl)-l(4-fluorophenyl)-4-oxobutyl-1,2,3,6-tetrahydropyridine (HPTP). The aim of this study was to examine the metabolism of HPTP in baboons in order to establish its appropriateness for a primate model of HPinduced neurotoxicity. HP produced excessive sedation which precluded its long term use. Twenty-four hour urine samples were collected from four control and four HPTP-treated animals after I, 3 and 5 months of treatment (8 mg/kg injected intramuscularly three times per week). Samples were analyzed for HPTP using a newly developed high performance liquid chromatography assay, as well as for HPP+ and RHPP+ using the method of Eyles et al. [I]. The major metabolite of HPTP was identified as RHPTP using liquid chromatography tandem mass spectrometry. In addition a glucuronide metabolite of RHPTP was also identified. HPP+ and RHPP + were present in low concentrations. This study demonstrates that there are similarities in the metabolism of HPTP in baboons and of HP in humans in that both are highly metabolised, converted to a reduced metabolite and oxidized to two potentially neurotoxic pyridinium species. Consequently, the HPTP-treated baboon warrants further investigation as an animal model of HP-induced neurotoxicity. [I] [I] Eyles, D et al (1994), ClinPharm Ther, 56 (5),512-520.
I P-2-4!
Mitochondrial Toxicity of Haloperidol and its Metabolites
H.R. McLennan 2, M. Degli Esposti 3, 1.J. McGrath I , S.M. Pond 2. I Clinical Studies Unit, Walston Park Hospital, Australia; 2 Dept of Medicine, Univ of Queensland, Princess Alexandra Hospital, Australia; 3 Centre for Molecular Biology and Medicine, Monash University, Australia Although haloperidol (HP) is one of the drugs that has revolutionised the treatment, of schizophrenia, it also causes severe, persistent extrapyramidal side effects such as tardive dyskinesia and parkinsonism. The mechanisms of these side-effects are unknown. One animal model of parkinsonism is based on the neurotoxicity of l-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP). MPTP is metabolised in glial cells to l-methyl-4-phenylpyridinium (MPJ>'") which is taken up selectively by the dopamine transporter and then by mitochondria in which it inhibits site I in the electron transport chain (ETC) and causes cell death. Recently, we have identified two pyridinium metabolites of HP in patients. These are 4-(4-chlorophenyl)-1-4-fluorophenyl-I-4-oxobutylpyridinium (HPJ>'") and 4-(4-chlorophenyl)-1-4-(4-f1uorophenyl)-4-hydroxybutylpyridinium (RHPP+). Proposed tetrahydropyridine intermediates of these are 4-(4-chlorophenyl)-1-4-fluorophenyl-4-oxobutyl-l ,2.3,6-tetrahydropyridine (HPTP) and the reduced analogue, RHPTP. The aim of this study was to examine whether HP and its metabolites, which are structural analogues of MPTP and MPP+, are toxic to mitochondria in a manner similar to MPP+. In the intact rat liver mitochondria, HPJ>'", RHPP+, HPTP and RHPTP inhibited site I of the ETC more potently than MPP+. HP and its major piperidinol metabolite, reduced haloperidol (RHP), did not inhibit site \. HPP+, RHPJ>'", HPTP and RHPTP seemed to inhibit site 2 with similar potency, but none of the compounds inhibited site 3. Spectrophotometric assays were then used to measure the inhibition of these compounds in exposed mitochondria, and a fluorometric assay using a pH-sensitive dye 9-amino-6-chloro-2-methoxyacrydine (ACMA), to measure the effect on mitochondrial proton pumping activity. These compounds inhibited complex I of the ETC specifically. They also produced non-specific effects such as uncoupling and radical production which may contribute further to mitochondrial damage. The mitochondrial toxicity of HP and its metabolites, which is similar to that of MPTP, could explain some of the neurotoxic side effects of the drug.
P Poster Presentations flicting results on 3H_IMlbinding sites and aging, we investigated possible age-related changes in platelet 3H-Par binding. Twenty subjects bewteen 78 and 85 years of age and 20 young ones (bewteen 25 and 38 years og age) were included in the study. Human platelets and 3H-Par binding were carried out following Marazziti et al.'s method (1995). Statistical analysis was performed by means of the umpaired Student's test. There was no significant difference in 3H-Par binding parameters between elderly and young subjects, a finding that suggests that 3H-Par binding sites are not sensitive to aging, at variance with 3H-IMI binding sites.
IP-2-1 I Lack of Pharmacokinetic Interaction Between Buspirone and Haloperidol in Schizophrenic Patients
M.W. lann, H.F. Huang, T.P. Chang, 1.S. Chen, D.J. luang, S.K. Lin, Y.w.F. Lam, c.P. Chien, W.H. Chang. Mercer University, Taipei City Psychiatric Center and University of Texas at Austin Buspirone (B) is non-benzodiazepine anxiolytic agent that does not produce sedation and psychomotor impairment. Haloperidol (H) is a neuroleptic drug commonly used in the treatment of psychiatric disorders. These two drugs are likely to be co-administered in psychiatric patients. This study was conducted in two phases: I) an in-depth pharmacokinetic study (N '" 11) and 2) at steady-state condition (N '" 27). H was assay by the HPLC with EC detection. The lower limit of detection was 0.4 ng/ml with CV less than 10% at 2-20 ng.m\. H doses ranged from 10-40 mg/day and B doses 10 mg TID. HL plasma levels (Cps) were obtained over a 24 hour time period in phase I. During phase 2, H Cps were measured at baseline and weeks 2 and 6. No significant changes were found in the pharmacokinetic parameters of H during B co-administration in phase I. H clearance (CLIF) '" 0.85 Llhrlkg vs. H + B CLIF '" 0.82 Llhrlkg. During phase 2, steady-state mean H Cp's remained unchanged during the addition of B. Mean H Cps at baseline, weeks 2 and 6 were 12.7 mg/ml, 12.7 ng/ml, and 13.6 ng/ml, respectively. These results indicate that addition of B does not significantly alter H disposition.
I P-2-21
Effect of Rifampin on Plasma Concentrations and Clinical Responses of Haloperidol in Schizophrenics 1.1.Woo, Y.H. Kim, r.c. Shim, 1.G. Shin, S.G. Shin. Departments of Psychiatry & Pharmacology, Seoul Nat'l Univ. Hosp. & lnje Univ. Hosp, Seoul, Korea
We assessed the changes of plasma haloperidol (HAL) concentrations and clinical responses repeatedly up to 4 wks after coadministration or discontinuation of rifampin (RIP) in 12 schizophrenic patients taking HAL alone (group I) and 5 schizophrenic patients taking HAL with antituberculotic drugs (group II). After coadministration of RIP in the group I, daily through concentrations decreased to 63% of baseline level by day 3,41.3% by day 7 and 30% by day 28. Conversely, after discontinuation of RIF in the group II, plasma HAL concentrations increased to 140.7% of baseline level by day 3, 228.7% by day 7 and 329% by day 28. The change in the BPRS score by 30% or greater was considered as a positive clinical response due to drug interaction. Using this criterion, 50% of the patients responded according to the BPRS total score and 25% of those responded according to the score of BPRS subscale for psychiatric symptoms in the group I. No positive response was observed in the group II. These results strongly suggest that RIF interacts with plasma HAL concentrations and affects the clinical response of HAL, and careful monitoring should be considered in case of coadministration or discontinuation of RIF in schizophrenics taking HAL.
IP-2-3!
The Quantitative Analysis of a Haloperidol Derivative andIts Neurotoxic Metabolites in Baboons
K. Avent I, C. Van der Schyf ", D. Eyles 3, N. Castagnoli 2, S. Pond I. I Dept ofMedicine, Univ ofQueensland, Australia; 2 Dept ofChemistry, Virginia Polytechnic, USA; 3 Clinical Studies Unit, Walston Park Hospital, Australia Haloperidol (HP) is a commonly used neuroleptic drug which produces extrapyramidal syndromes such as tardive dyskinesia (TD)
and drug-induced parkinsonism. It has been reported previously that two pyridinium metabolites, 4-(4-chlorophenyl)-I-(4-fluorophenyl)-4oxobutyl-pyridinium (HPJ>'") and 4-(4-chlorophenyl)-I-(4-fluorophenyl)4-hydroxybutyl-pyridinium (RHPP+), which are similar in structure to the well characterized parkinsonian agent l-methyl-4-phenyl pyridinium (MPP+), are found in the urine and blood of patients treated with HP [I]. This metabolism is presumed to occur via 4-(4-chlorophenyl)-l(4-fluorophenyl)-4-oxobutyl-1,2,3,6-tetrahydropyridine (HPTP). The aim of this study was to examine the metabolism of HPTP in baboons in order to establish its appropriateness for a primate model of HPinduced neurotoxicity. HP produced excessive sedation which precluded its long term use. Twenty-four hour urine samples were collected from four control and four HPTP-treated animals after I, 3 and 5 months of treatment (8 mg/kg injected intramuscularly three times per week). Samples were analyzed for HPTP using a newly developed high performance liquid chromatography assay, as well as for HPP+ and RHPP+ using the method of Eyles et al. [I]. The major metabolite of HPTP was identified as RHPTP using liquid chromatography tandem mass spectrometry. In addition a glucuronide metabolite of RHPTP was also identified. HPP+ and RHPP + were present in low concentrations. This study demonstrates that there are similarities in the metabolism of HPTP in baboons and of HP in humans in that both are highly metabolised, converted to a reduced metabolite and oxidized to two potentially neurotoxic pyridinium species. Consequently, the HPTP-treated baboon warrants further investigation as an animal model of HP-induced neurotoxicity. [I] [I] Eyles, D et al (1994), ClinPharm Ther, 56 (5),512-520.
I P-2-4!
Mitochondrial Toxicity of Haloperidol and its Metabolites
H.R. McLennan 2, M. Degli Esposti 3, 1.J. McGrath I , S.M. Pond 2. I Clinical Studies Unit, Walston Park Hospital, Australia; 2 Dept of Medicine, Univ of Queensland, Princess Alexandra Hospital, Australia; 3 Centre for Molecular Biology and Medicine, Monash University, Australia Although haloperidol (HP) is one of the drugs that has revolutionised the treatment, of schizophrenia, it also causes severe, persistent extrapyramidal side effects such as tardive dyskinesia and parkinsonism. The mechanisms of these side-effects are unknown. One animal model of parkinsonism is based on the neurotoxicity of l-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP). MPTP is metabolised in glial cells to l-methyl-4-phenylpyridinium (MPJ>'") which is taken up selectively by the dopamine transporter and then by mitochondria in which it inhibits site I in the electron transport chain (ETC) and causes cell death. Recently, we have identified two pyridinium metabolites of HP in patients. These are 4-(4-chlorophenyl)-1-4-fluorophenyl-I-4-oxobutylpyridinium (HPJ>'") and 4-(4-chlorophenyl)-1-4-(4-f1uorophenyl)-4-hydroxybutylpyridinium (RHPP+). Proposed tetrahydropyridine intermediates of these are 4-(4-chlorophenyl)-1-4-fluorophenyl-4-oxobutyl-l ,2.3,6-tetrahydropyridine (HPTP) and the reduced analogue, RHPTP. The aim of this study was to examine whether HP and its metabolites, which are structural analogues of MPTP and MPP+, are toxic to mitochondria in a manner similar to MPP+. In the intact rat liver mitochondria, HPJ>'", RHPP+, HPTP and RHPTP inhibited site I of the ETC more potently than MPP+. HP and its major piperidinol metabolite, reduced haloperidol (RHP), did not inhibit site \. HPP+, RHPJ>'", HPTP and RHPTP seemed to inhibit site 2 with similar potency, but none of the compounds inhibited site 3. Spectrophotometric assays were then used to measure the inhibition of these compounds in exposed mitochondria, and a fluorometric assay using a pH-sensitive dye 9-amino-6-chloro-2-methoxyacrydine (ACMA), to measure the effect on mitochondrial proton pumping activity. These compounds inhibited complex I of the ETC specifically. They also produced non-specific effects such as uncoupling and radical production which may contribute further to mitochondrial damage. The mitochondrial toxicity of HP and its metabolites, which is similar to that of MPTP, could explain some of the neurotoxic side effects of the drug.