Quantitation of Haloperidol, Fluphenazine, Perphenazine, and Thiothixene in Serum or Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Haloperidol, fluphenazine, perphenazine, and thiothixene are "typical" antipsychotic drugs that are used in the treatment of schizophrenia and other psychiatric disorders. The monitoring of the use of these drugs has applications in therapeutic drug monitoring and overdose situations. LC-MS/MS is used to analyze plasma/serum extracts with deuterated analog of imipramine as the internal standard to ensure accurate quantitation and control for any potential matrix effects. Positive ion electrospray is used to introduce the analytes into the mass spectrometer. Selected reaction monitoring of two product ions for each analyte allows for the calculation of ion ratios which ensures correct identification of each analyte, while a matrix-matched calibration curve is used for quantitation.

Quantitation of fluphenazine in equine serum following fluphenazine decanoate administration.

Fluphenazine, a potent antipsychotic used to treat schizophrenia in humans, is used in racehorses as a performance-enhancing drug, and for that reason it has been banned by the Association of Racing Commissioners International. A liquid chromatography-tandem mass spectrometry method for detecting and quantitating fluphenazine in equine serum was developed and validated. The method was then employed to quantitate fluphenazine in serum samples collected from three study horses after intramuscular injection of fluphenazine decanoate. Stability testing showed that fluphenazine is stable in unextracted and processed samples as well as samples that have been subjected to up to three freeze-thaw cycles. The limit of detection and lower limit of quantitation of fluphenazine were determined to be 0.05 and 0.1 ng/mL, respectively. Precision was evaluated based on one-way analysis of variance of replicate quality control samples and was determined to be 27.2% at the 0.2 ng/mL level and 18.1% at the 2 ng/mL level. Bias was determined to be 0.55% at the 0.2 ng/mL level and 3.66% at the 2 ng/mL level. In two of three horses, fluphenazine was detected in serum up to 14 days post-administration. The highest detected concentration of fluphenazine in serum was 1.4 ng/mL.

Simultaneous UPLC-MS/MS assay for the detection of the traditional antipsychotics haloperidol, fluphenazine, perphenazine, and thiothixene in serum and plasma.

BACKGROUND: Most antipsychotic drugs that are commonly prescribed in the USA are monitored by liquid and gas chromatographic methods. Method performance has been improved using ultra high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). A rapid and simple procedure for monitoring haloperidol, thiothixene, fluphenazine, and perphenazine is described here. METHOD: Antipsychotic drug concentrations in serum and plasma were determined by LCMS/MS (Waters Acquity UPLC TQD). The instrument is operated with an ESI interface, in multiple reaction monitoring (MRM), and positive ion mode. The resolution of both quadrupoles was maintained at unit mass with a peak width at half height of 0.7amu. Data analysis was performed using the Waters Quanlynx software. Serum or plasma samples were thawed at room temperature and a 100µL aliquot was placed in a tube. Then 300µL of precipitating reagent (acetonitrile-methanol [50:50, volume: volume]) containing the internal standard (0.12ng/µL Imipramine-D3) was added to each tube. The samples were vortexed and centrifuged. The supernatant was transferred to an autosampler vial and 8µL was injected into the UPLC-MS/MS. Utilizing a Waters Acquity UPLC HSS T3 1.8µm, 2.1×50mm column at 25ºC, the analytes were separated using a timed, linear gradient of acetonitrile and water, each having 0.1% formic acid added. The column is eluted into the LC-MS/MS to detect imipramine D3 at transition 284.25>89.10, haloperidol at 376.18>165.06, thiothixene at 444.27>139.24, fluphenazine at 438.27>171.11, and perphenazine at 404.19>143.07. Secondary transitions for each analyte are also monitored for imipramine D3 at 284.25>193.10, haloperidol at 376.18>122.97, thiothixene at 444.27>97.93, fluphenazine at 438.27>143.08, and perphenazine at 404.19>171.11. The run-time is 1.8min per injection with baseline resolved chromatographic separation. RESULTS: The analytical measurement range was 0.2 to 12.0ng/mL for fluphenazine and perphenazine, and was 1 to 60.0ng/mL for haloperidol and thiothixene. Intra-assay and inter-assay imprecisions (CV) were less than 15% at two concentrations for each analyte. CONCLUSIONS: By utilizing a LC-MS/MS method we combined two previously established analytical assays into one, yielding a 75% time-savings on set-up, and a significantly shortened analytical run-time. These changes reduced the turn-around time for analysis and eliminated interference issues resulting in fewer injections and increased column lifetime.

Simultaneous chemiluminescence determination of promazine and fluphenazine using support vector regression.

In this work, chemiluminescence (CL) behaviors of two selected phenothiazines, namely promazine and fluphenazine hydrochloride, were investigated for their simultaneous determination using oxidation of Ru(bipy)(3)(2+) by Ce(4+) ions in acidic media. This method is based on the kinetic distinction of the CL reactions of fluphenazine and promazine with Ru(bipy)(3)(2+) and Ce(4+) system in a sulfuric acid medium. Least square support vector regression models were constructed for relating concentrations of both compounds to their CL profiles. The parameters of the model consisting of sigma(2) and gamma were optimized using all possible combinations of sigma(2) and gamma to select the model with the minimum root mean square cross validation. Under optimized conditions, the univariate calibration curve was linear over the concentration ranges of 0.4-30.0 microg mL(-1) and 0.07-5.0 microg mL(-1) with detection limits of 0.1 microg mL(-1) and 0.04 microg mL(-1) for promazine and fluphenazine, respectively. The influence of potential interfering substances on the determination of promazine and fluphenazine were studied. The proposed method was used for simultaneous determination of both compounds in synthetic mixtures and in spiked human plasma.

Spectrofluorometric determination of olanzapine and fluphenazine hydrochloride in pharmaceutical preparations and human plasma using eosin: application to stability studies.

A simple, rapid, and sensitive spectrofluorometric method has been developed for the determination of olanzapine (OLZ) and fluphenazine hydrochloride (FPZ HCI). The proposed method is based on the quantitative quenching effect of the studied drugs on the native fluorescence of eosin at pH 3.4 and 3.2 for OLZ and FPZ HCI, respectively. The fluorescence was measured at 547 nm after excitation at 323 nm. The fluorescence-concentration plots were rectilinear over the range of 0.05-1.0 and 0.10-1.0 microg/mL, with lower detection limits of 1.8 x 10(-3) and 1.2 x 10(-3) microg/mL, for OLZ and FPZ HCI, respectively. The proposed method was successfully applied to the analysis of commercial tablets and ampules containing the drugs, and the results were in good agreement with those obtained with reference methods. The proposed method was further applied to the determination of OLZ in spiked human plasma. The mean recovery was 98.62 +/- 0.24% (n = 4). The method was also used for stability studies of FPZ HCI upon oxidation with hydrogen peroxide, and the kinetics of the reaction were studied. A proposal for the reaction pathway was postulated.

Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates.

The pharmacokinetics of antipsychotic drugs has become an integral part in understanding their pharmacodynamic activity and clinical effects. In addition to metabolism aspects, carrier-mediated transport, particularly secretion by ABC transporters, has been discussed as potentially relevant for this group of therapeutics. In this study, the psychoactive compounds perphenazine, flupentixol, domperidone, desmethyl clozapine, haloperidol, fluphenazine, fluvoxamine, olanzapine, levomepromazine, perazine, desmethyl perazine, clozapine, quetiapine and amisulpride were characterized in terms of P-glycoprotein (P-gp) affinity and transport. Experimental methods involved a radioligand displacement assay with [3H]talinolol as radioligand and transport--as well as transport inhibition--studies of the P-gp substrate [3H]talinolol across Caco-2 cell monolayers. In addition, the physicochemical descriptors log P and deltalog P were determined to test potential correlations between transporter affinity and lipophilicity parameters. All of the tested antipsychotics showed affinity to P-gp albeit their IC50 values (concentration of competitor that displaced 50% of the bound radioligand) differed by a factor exceeding 1000, when compared using the transport inhibition assay. From the group of P-gp substrates, amisulpride and fluphenazine were selected for in-vivo drug-drug interaction studies in rats to demonstrate the in-vivo relevance of the in-vitro findings. Compounds were administered by intraperitoneal injection either alone or in combination with 50 mg kg(-1) ciclosporin. The concentration versus time profiles for both drugs were followed in serum as well as in brain tissues. Significant differences between the treatments with the antipsychotic alone versus the combination of antipsychotic with ciclosporin were found for amisulpride. The distribution of amisulpride to the brain was increased and systemic serum levels were likewise increased indicating decreased systemic clearance for the combination regimen. For fluphenazine, systemic levels with and without co-administration of ciclosporin were comparable while higher brain-to-serum concentration ratios were found after co-administration of ciclosporin. The findings are explained on the basis of the limited contribution of P-gp-mediated transport to the elimination of fluphenazine and to a direct effect with respect to its distribution into the brain.

Increased incidence of dyskinesias and other behavioral effects of re-exposure to neuroleptic treatment in social colonies of Cebus apella monkeys.

RATIONALE: Typical neuroleptic medications are still administered to as many as 40% of patients receiving antipsychotic treatment in the US. Intermittent administration or interruption of long-term neuroleptic medication for schizophrenia may increase the incidence of human tardive dyskinesias, and similarly may produce increasingly marked motor side-effects, parkinsonism, and other behavioral pathologies in non-human primates. OBJECTIVES AND METHODS: Given these similarities, we addressed the issue of prolonged and intermittent typical neuroleptic treatment and dopaminergic function during a 5-year, multi-phase study with social colonies of Cebus apella monkeys. In the previously reported phase 1, we examined the effects of 48 weeks of exposure to, followed by withdrawal from, fluphenazine decanoate (FPZ). Phase 3 reported here examined the effects of 18 weeks of re-exposure to FPZ in these same monkeys, 91 weeks after discontinuation of their phase 1 FPZ treatment. RESULTS: Analysis of blood plasma FPZ indicated levels of 0.22+/-0.08 ng/ml for the six injections during the re-exposure period (n=54), comparable to the 0.24+/-0.07 ng/ml levels measured during our original treatment with this dose. Acute dyskinesias and dystonias increased by 300% upon re-exposure to FPZ; 15 of 18 FPZ-treated animals exhibited oral-buccal dyskinesias and all exhibited torticollis or retrocollis. Retreatment with FPZ was also associated with highly significant reductions in Self- and Environment-Directed Behavior and Directed Affiliation, effects similar to those seen during the original phase 1 FPZ treatment. Although FPZ re-treatment was associated with a significant reduction in Directed Aggression (an effect that was more robust than that observed during phase 1), in phase 3, we again observed an increase in Directed Aggression during early drug discontinuation when animals were in a stress-inducing situation. CONCLUSIONS: These results both support our phase 1 conclusion that typical neuroleptic medications may contribute to negative symptoms of schizophrenia and provide additional evidence for the possibility of increased aggression in stressful situations when medication is discontinued. Additionally, the results indicate that intermittent treatment with typical neuroleptics may dramatically increase the incidence of dystonias and dyskinesias.

The roles of depot injection sites and proximal lymph nodes in the presystemic absorption of fluphenazine decanoate and fluphenazine: ex vivo experiments in rats.

PURPOSE: The release and presystemic absorption of fluphenazine and its decanoate ester from intramuscular depots were investigated. METHODS: Rats were sacrificed in groups of three at various times after injection of drug or prodrug in sesame oil. Muscle tissues at the injection sites and various lymph nodes were excised. Blood (plasma) was harvested by cardiac puncture. RESULTS: Following administration of fluphenazine decanoate, the amount of prodrug at the sites of injection declined exponentially (half-life 3.4 days). Highest concentrations of drug and prodrug were found in iliac and hypogastric lymph nodes nearest to injection sites in which both analytes were detectable 28 days post dose. The half-life for the decline of fluphenazine from lymph nodes (4.6 days) was similar to that from plasma (4.3 days). Following administration of fluphenazine base, only 2.8% of the dose remained at the sites of injection after 2 days. Concentrations of drug in iliac and hypogastric lymph nodes were comparable to those in distal lymph nodes. Fluphenazine concentrations in the lymphatic tissues decreased at about the same rate as plasma concentrations. CONCLUSIONS: The rate limiting step appeared to be slow partitioning of the decanoate from oily deposits at the injection site and proximal lymph nodes with subsequent hydrolysis of the ester group.

Tardive dyskinesia and serum iron indices.

BACKGROUND: This study was undertaken to evaluate whether peripheral (serum) markers of iron status are associated with severity of the choreoathetoid movements seen in tardive dyskinesia (TD). METHODS: Serum iron indices (ferritin, iron, and total iron binding capacity) and fluphenazine levels were measured in a group of 30 male DSM-III diagnosed schizophrenic patients chronically treated with fluphenazine decanoate. The severity of choreoathetoid movements was assessed with the Abnormal Involuntary Movement Scale (AIMS), and akathisia was assessed with the Barnes scale. RESULTS: A significant positive correlation was observed between AIMS scores and serum ferritin. This relationship remained significant after controlling for age and plasma fluphenazine levels. No significant correlations were observed between serum iron or total iron binding capacity and choreoathetoid movement ratings. There were no significant associations between serum iron indices and akathisia ratings. CONCLUSIONS: The data suggest that choreoathetoid movements are associated with serum ferritin levels in chronically medicated male schizophrenic patients. This relationship does not seem to be caused by an association of these variable with age or plasma fluphenazine levels. In addition, the relationship seems to be specific, since other iron indices and another extrapyramidal side effect (akathisia) do not demonstrate a similar relationship. In view of reports that antipsychotic medications change normal iron metabolism and increase iron uptake into the brain, the current results could be interpreted to suggest that serum ferritin levels may be a risk factor for TD in patients treated with "classic" antipsychotic medications.

Studies on the mechanism of absorption of depot neuroleptics: fluphenazine decanoate in sesame oil.

PURPOSE: The purpose of the present study was to investigate the pharmacokinetic characteristics of fluphenazine (FLU) and its decanoate (FLU-D) after intravenous and intramuscular administration to dogs. METHODS: A group of four beagle dogs was used in all intravenous and intramuscular experiments, with washout periods of no less than three months between doses. RESULTS: After intravenous FLU-D, the pharmacokinetics of the prodrug (mean +/- SD) were as follows: Clearance (CL) 42.9 +/- 6.3 L/h; terminal half-life (t1/2) 3.5 +/- 0.8 h; volume of distribution (Vd) 216 +/- 61 L. The fractional availability of FLU was 1.0 +/- 0.2. After intravenous FLU, the volume of distribution of FLU (51 +/- 17.8 L) was some 4 fold less than that of the prodrug. Simulations (Stella II) suggested that the rate limiting step was slow formation of FLU from the prodrug in the tissue compartment. After intramuscular FLU-D in sesame oil, the apparent t1/2 of FLU was 9.7 +/- 2.0 days whereas after intramuscular FLU base in sesame oil, the apparent t1/2 was only 7.7 +/- 3.4 h showing that the absorption of FLU itself from the intramuscular site and proximal lymph nodes is relatively rapid. CONCLUSIONS: The rate limiting step after intramuscular FLU-D appeared to be the slow partitioning of the prodrug out of the sesame oil at the injection site and in proximal lymph nodes.

Effects of dopamine agonists on Cebus apella monkeys with previous long-term exposure to fluphenazine.

Sixty-one weeks after 48 weeks of treatment with fluphenazine decanoate or placebo, 37 socially living Cebus apella monkeys were evaluated for differences in dopaminergic sensitivity by exposure to 0.75 mg/kg, i.m. of amphetamine (AMPH) (indirect agonist) and apomorphine (APOM) (direct agonist). The fluphenazine-treated animals differed (p < or = 0.05) from control animals on some hourly measures of composite behavioral variables (CBVs). Animals exposed to fluphenazine showed a greater decrease in the aggressiveness CBV and a smaller decrease in self- and environment-directed behaviors than placebo animals. CBVs for normal locomotion and directs affiliation showed no significant differences. The fluphenazine-treated group showed greater agonist induction of stereotypic behavior (p < or = 0.01), and larger decreases in prolactin response to AMPH (p < or = 0.05). Our findings indicate that following extended treatment with an antipsychotic there is increased sensitivity to dopamine, as evidenced by stereotypies and possibly hypophyseal responsiveness.

Sensitive method for the simultaneous measurement of fluphenazine decanoate and fluphenazine in plasma by high-performance liquid chromatography with coulometric detection.

A highly sensitive and specific high-performance liquid chromatographic method with coulometric detection was developed for the simultaneous assay of fluphenazine decanoate and fluphenazine in plasma. The extraction and sample clean-up procedures are simple, rapid to execute, yet yield chromatograms relatively free of any interference from endogenous plasma constituents, such that the extraordinary sensitivity of the coulometric detector can be exploited fully. This is the first analytical procedure for the simultaneous determination of fluphenazine decanoate and fluphenazine. The detection limits for both fluphenazine decanoate and fluphenazine were 0.1 ng/ml plasma and the limits of quantitation were 0.25 ng/ml plasma. Standard curves from 0.25 to 10 ng/ml were linear with coefficients of variation < 10%. The method was applied to measure plasma levels of fluphenazine decanoate and fluphenazine in patients under medication with 25-50 mg biweekly intramuscular (i.m.) injections of fluphenazine decanoate. It was possible to monitor the plasma levels of fluphenazine in all cases. Fluphenazine decanoate was present in measurable concentration in the plasma of 4 out of 5 patients who received biweekly i.m. injections of 50 mg fluphenazine decanoate. In a pilot experiment with a dog, the method was used to follow fluphenazine decanoate and fluphenazine plasma levels up to 13 days, at least, after i.m. single dose (10 mg/kg).

Fluphenazine plasma levels, dosage, efficacy, and side effects.

OBJECTIVE: The authors sought to determine whether fluphenazine dose or plasma level predicts clinical improvement or side effects during acute treatment. METHOD: Oral fluphenazine was given in fixed, randomized, double-blind doses (10, 20, or 30 mg/day) for 4 weeks to 72 inpatients with acute schizophrenic exacerbations. Outcome measures included percentage improvement in ratings of positive symptoms (hallucinations, delusions, and thought disorder), percentage improvement in negative symptoms, and maximum score for extrapyramidal symptoms. Response was defined as an improvement in positive symptoms of 40% or more. RESULTS: The 42 responders had a shorter duration of illness, less chronic course, and lower rate of akathisia. Plasma level and dose did not differentiate responders and nonresponders, but they did predict percentage improvement in positive symptoms within the responder subgroup. Akathisia was more common and extrapyramidal symptoms were more severe at higher plasma levels. CONCLUSIONS: Responders showed the greatest improvement at fluphenazine plasma levels above 1.0 ng/ml and doses above 0.20-0.25 mg/kg per day. Since the literature suggests that optimal plasma levels are similar during acute and maintenance treatment, monitoring of plasma levels may thus be useful. Conditions for applying the "responder-only" analytic strategy in future studies are discussed.

Monitoring plasma levels of fluphenazine during chronic therapy with fluphenazine decanoate.

This study was conducted to examine the interpatient variability in steady-state plasma concentrations of fluphenazine by repeat depot intramuscular administration, and to determine the relationship between these concentrations and clinical state. Steady-state pre-dose concentrations of fluphenazine in plasma were measured using a sensitive and specific gas chromatography/mass spectrometry (GC/MS) assay in 24 patients with schizophrenia who were receiving continuous treatment with depot intramuscular fluphenazine decanoate. Clinical response was measured using the Andreasen Scale for positive and negative symptoms. Steady-state plasma concentrations of fluphenazine ranged from undetectable (< 0.1 ng/ml) to 27.9 ng/ml, with a median of 0.5 ng/ml. No significant associations were found between plasma concentration and dosage, or age and sex of the patient. Steady-state plasma concentrations in patients taking anticholinergic agents were significantly higher than in patients not receiving such drugs (P < 0.05 by Mann-Whitney U-test). Poorer control, expressed as the sum of the negative symptom scores or the sum of the positive and negative symptom scores, was related to higher log transformed plasma concentration of fluphenazine and higher fluphenazine decanoate dosage. The log transformed plasma concentrations of fluphenazine and the fluphenazine decanoate dosages were weakly related. Patients receiving another antipsychotic drug in addition to fluphenazine decanoate tended to have poorer clinical control and higher dosages of fluphenazine decanoate. These results indicate the useful role that plasma level monitoring can fulfil in identifying patients who are therapy-resistant despite high plasma levels.

A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia.

Following a 2-week placebo lead-in, schizophrenic patients were randomly assigned to fluoxetine 20 mg/day or placebo added to depot neuroleptic for a 6-week, double blind trial. All patients had received a stable dose of depot neuroleptic for at least 6 months and did not meet criteria for depression. Serum samples were obtained at baseline and at weeks 4 and 6. Scores on the negative symptom subscale of the Brief Psychiatric Rating Scale (BPRS) were significantly lower at week 6, controlling for baseline scores, in patients receiving fluoxetine (n = 20) compared to patients receiving placebo (n = 21). Measures of psychosis, depression, global functioning and extrapyramidal symptoms (EPS) did not differ between groups at week 6. Fluoxetine administration was associated with a mean 65% increase in serum fluphenazine concentrations in 15 patients and a mean 20% increase in serum haloperidol concentrations in three patients. The change in negative symptoms at week 6 did not correlate with serum concentrations of fluoxetine or norfluoxetine, but did inversely correlate with S-norfluoxetine, an active stereoisomer of fluoxetine. For these chronically ill patients, fluoxetine significantly improved negative symptoms and did not worsen EPS, despite causing substantial elevation in serum concentrations of neuroleptics.

Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia.

This review covers some recent work on: 1. The effects of route of administration on the pharmacokinetics of fluphenazine and some of its metabolites; 2. The clinical pharmacokinetics of fluphenazine in acute patients medicated with oral fluphenazine; 3. The clinical pharmacokinetics of haloperidol in acute patients medicated with oral haloperidol; 4. The clinical pharmacokinetics of fluphenazine in the maintenance of individuals with chronic schizophrenia with fluphenazine decanoate; 5. A systematic dose reduction study in maintenance treatment refractory patients with oral haloperidol. A study in which plasma levels of fluphenazine and fluphenazine sulfoxide were measured in a group of DSM-III-R patients with schizophrenia before and after switching from oral fluphenazine to depot fluphenazine, decanoate revealed much higher levels of fluphenazine sulfoxide with oral medication compared with those found with depot fluphenazine. These data illustrate the effect of "first pass" metabolism after oral fluphenazine. Thus in a group of 33 patients randomly assigned to receive 5 mg, 10 mg or 25 mg oral fluphenazine daily, steady state plasma fluphenazine levels at each dose were significantly lower that those of fluphenazine sulfoxide or 7-hydroxy-fluphenazine, although there were no significant differences between the levels of fluphenazine and fluphenazine N4-oxide. On the other hand, plasma levels of the parent drug were significantly higher than those of any metabolite in a corresponding group of patients at steady state on depot medication. These observations underscore the importance of route dependent differences in the pharmacokinetics of fluphenazine which can lead to problems when switching patients from oral to depot neuroleptics. The concept of "disabling side-effects" is an important development in understanding relationships between plasma levels of neuroleptic drugs and clinical response in patients with schizophrenia. Risk-benefit analysis shows clearly that evaluation of relationships between plasma levels and clinical response must take into account the consequences of side-effects which the patient feels have a negating effect on therapy. Emerging data on putative therapeutic plasma level ranges in maintenance therapy are potentially important and may be particularly useful in the maintenance of patients on low dose therapy. It is noteworthy that in a carefully executed dose reduction study in treatment resistant patients under medication with haloperidol, the mean lowest effective dose (8.7 ng/mL) lay within the optimal therapeutic range (5 ng/mL to 12 ng/mL) found in acutely psychotic patients. The study showed that gradual dose reduction of neuroleptic was possible in chronic treatment resistant patients with schizophrenia who were originally thought by ward staff to require high doses of neuroleptic.(ABSTRACT TRUNCATED AT 400 WORDS)

Radioimmunoassay for 7-hydroxy metabolite of fluphenazine and its application to plasma level monitoring in schizophrenic patients treated long term with oral and depot fluphenazine.

Immunization of New Zealand white rabbits with a bovine serum albumin conjugate of 7-hydroxy-N-carboxyethyl-N-deshydroxyethylfluphenazine produced highly specific antisera for 7-hydroxyfluphenazine (7-OHFLU). A radioimmunoassay (RIA) was developed using antisera from one of the rabbits that enabled for the first time the determination of plasma levels of 7-OHFLU, an active metabolite of fluphenazine (FLU), in patients treated with oral FLU dihydrochloride or i.m. FLU decanoate. The assay method provided sufficient sensitivity to determine accurately 20 pg of 7-OHFLU in 200 microliters (0.1 ng/ml) of plasma with a coefficient of variation of < 10%. The antiserum used in the RIA for 7-OHFLU demonstrated negligible cross-reactivity with FLU and its metabolites such as FLU sulfoxide, N-deshydroxyethylFLU, FLU N4'-oxide, N-deshydroxyethyl-7-OHFLU, and 7-O-glucuronide of FLU and also with other antipsychotic agents and commonly coadministered drugs. The 7-OHFLU was present in measurable amounts in all plasma samples obtained at 4-week intervals from patients receiving a daily oral dose of 5 (n = 10), 10 (n = 13), or 20 (n = 14) mg of FLU dihydrochloride. Large interindividual variations in the plasma level of FLU and 7-OHFLU were noted and the mean plasma levels ratios of 7-OHFLU/FLU at these doses were 2.07 +/- 1.08, 2.07 +/- 1.13, and 2.02 +/- 0.82, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of plasma fluphenazine levels to treatment response and extrapyramidal side effects in first-episode schizophrenic patients.

OBJECTIVE: The aim of this study was to determine the relation between plasma fluphenazine levels and clinical response in first-episode schizophrenic patients. METHOD: Data from 36 first-episode schizophrenic or schizoaffective inpatients diagnosed according to the Research Diagnostic Criteria were evaluated. The patients received open, standardized treatment with fluphenazine, 20 mg/day, for at least 4 weeks. Psychopathology was assessed biweekly, and plasma fluphenazine levels were ascertained weekly. Patients were classified as responders or nonresponders, and correlations between their neuroleptic levels and ratings of psychopathologic and extrapyramidal symptoms were computed. RESULTS: Plasma fluphenazine levels for weeks 1 through 4 were significantly correlated with each other but were not correlated with age, gender, diagnosis, or race. Mean neuroleptic levels (weeks 3 and 4) were not different between responders and nonresponders and were not correlated with measures of psychopathology or extrapyramidal symptoms. CONCLUSIONS: These results do not indicate an association between plasma fluphenazine levels and response to treatment or extrapyramidal side effects in first-episode schizophrenia. The disparity between the results of this study and those of previous studies may be due to methodological differences or to a biologically based difference between first-episode and chronic patients.

Clinical perspectives of some neuroleptics through development and application of their assays.

Attempts to investigate relationships between plasma levels of neuroleptics and therapeutic outcome in schizophrenic patients have been hampered due to such factors as the chemical nature of these drugs, their metabolism, and the very heterogeneous nature of the disease states. Two clinical studies are described that investigate the relationship between plasma levels of fluphenazine (FLU) and its metabolites and therapeutic outcome in schizophrenic patients. In the first of these studies the levels of FLU and fluphenazine sulfoxide (FLUSO) in schizophrenics receiving either 5 or 25 mg of fluphenazine decanoate (FLUD) intramuscularly every 2 weeks were monitored. Patients given 25 mg of FLUD required 3 months to reach plasma level steady state. The results suggest that such patients, when being switched from the oral to the depot formulation of FLU, should continue to receive oral supplementation during the 1st 3 months after conversion. The relationship between log-transformed plasma levels at 26 and 38 weeks with subsequent psychotic exacerbation was investigated with the use of logistic regression and survival analysis. Both demonstrated significant relationships between FLU plasma levels and a risk of psychotic exacerbation at 26 and 38 weeks. The possibility of any correlations between neurological side effects and plasma concentrations were also investigated, with statistically significant correlations between FLU levels and akinesia found at 2 and 26 weeks. In the second of these studies the levels of FLU, FLUSO, 7-hydroxyfluphenazine (7-OHFLU), and fluphenazine N4'(-)-oxide (FLUNO) in schizophrenics receiving 5, 10, or 20 mg of oral fluphenazine dihydrochloride daily for 4 weeks were monitored. The relationships between log-transformed plasma levels, disabling side effects, and global improvement were examined by logistic regression for the 4-week period. The study showed a significant correlation between increases in both plasma levels and disabling side effects such that at a plasma level of 2.7 ng/ml, approximately 90% of acutely ill patients experienced disabling side effects. Conversely, the study also showed that at a plasma level of 0.67 ng/ml, 48% of patients experienced improvement without the development of disabling side effects. When relationships between metabolite levels, disabling side effects, and global improvement were examined by logistic regression, a stronger correlation between disabling side effects and FLUNO levels than between side effects and FLU levels was found.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma fluphenazine levels measured by high-performance liquid chromatography in patients treated with depot injections.

Fluphenazine (CAS 69-23-8) concentrations in plasma of schizophrenic patients after oral (fluphenazine hydrochloride, Moditen) or intramuscular (fluphenazine enanthate, Moditen Retard, or fluphenazine decanoate, Modecate) administration of drug were measured by means of high-performance liquid chromatography. The extracted compound was identified by gas chromatography with mass selective detector. Pharmacokinetics of fluphenazine has been studied.