Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients.

Background Oral prochlorperazine, a dopamine D2 receptor antagonist, is largely metabolized to sulphoxide, 7-hydroxylate and N-desmethylate by cytochrome P450s (CYPs). This study evaluated the influence of CYP genotype on the plasma dispositions of prochlorperazine and its metabolites and their relationships with antiemetic efficacy and prolactin elevation in cancer patients. Methods Forty-eight cancer patients treated with oral prochlorperazine were enrolled. Plasma prochlorperazine and its metabolites concentrations and serum prolactin concentration were determined at 12 h after the evening dosing. The genotypes of CYP2C19, CYP2D6 and CYP3A5 and the incidences of nausea and vomiting were investigated. Results The plasma concentrations of the prochlorperazine metabolites were weakly correlated with that of the parent drug. The CYP genotypes did not affect the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine and its metabolites were not associated with the incidences of nausea and vomiting. The incidence of vomiting was significantly higher in females than in males. The serum prolactin concentration was weakly correlated with the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine metabolites rather than the parent drug had a weaker relation to serum prolactin concentration. Conclusions The CYP genotypes did not affect the plasma dispositions of prochlorperazine and its metabolites. The prochlorperazine metabolites did not have a strong effect on antiemetic efficacy, while they were slightly associated with prolactin secretion in cancer patients.

Impact of genetic and non-genetic factors on clinical responses to prochlorperazine in oxycodone-treated cancer patients.

BACKGROUND: The contributions of DRD2 and OPRM1 genetic variants to clinical responses to prochlorperazine remain to be clarified in opioid-treated patients. We evaluated the clinical responses to prochlorperazine based on non-genetic and genetic factors in oxycodone-treated patients. METHODS: Seventy Japanese cancer patients starting oral prochlorperazine together with oxycodone were enrolled. Predose plasma prochlorperazine concentrations and serum prolactin concentrations were determined. The incidences of oxycodone-induced nausea and vomiting were monitored for 2weeks. RESULTS: Plasma prochlorperazine concentration and oxycodone daily dose were not associated with the incidences of nausea and vomiting. The incidence of nausea was significantly higher in the DRD2 TaqIA A1A2+A1A1 group than in the A2A2 group. The incidence of vomiting was significantly higher in females than in males. Before and after the prochlorperazine administration, the serum prolactin concentration was significantly higher in female patients than in male patients. The serum prolactin concentration was weakly correlated with prochlorperazine concentration and was significantly higher in the OPRM1 118AA group than in the AG+GG group. CONCLUSIONS: DRD2 TaqIA and female gender altered the prophylactic antiemetic efficacy of prochlorperazine. OPRM1 A118G together with plasma exposure of prochlorperazine and gender affected prolactin secretion in oxycodone-treated patients.

Simultaneous determination of prochlorperazine and its metabolites in human plasma using isocratic liquid chromatography tandem mass spectrometry.

Oral prochlorperazine (PCZ), an antiemetic, undergoes extensive first-pass metabolism. The study developed a simultaneous analytical method for PCZ and its major metabolites, prochlorperazine sulfoxide (PCZSO), N-demethylprochlorperazine (NDPCZ) and 7-hydroxyprochlorperazine (PCZOH), in human plasma using an isocratic liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Deproteinized plasma specimens were separated using a 3 µm particle size octadecylsilyl column, and the run time was 10 min. The calibration curves were linear over the concentration ranges of 0.01-40 µg/L for PCZ, NDPCZ and PCZOH, and 0.05-80 µg/L for PCZSO. The intra- and inter-assay precisions and accuracies were within 7.0 and 99-104% and within 9.0 and 99-105%, respectively. The lower limits of quantification in human plasma were 10 ng/L for PCZ, NDPCZ and PCZOH, and 50 ng/L for PCZSO. The validated method was applied to the determination of plasma samples in 37 cancer patients receiving PCZ. Large interindividual variations were observed in plasma concentrations of PCZ, PCZSO, NDPCZ and PCZOH (relative standard deviation, 89.4, 88.7, 86.4 and 78.2%, respectively). In conclusion, this simultaneous LC-MS/MS method with acceptable analytical performance can be helpful for evaluating the pharmacokinetics of PCZ, including the determination of its metabolites in cancer patients and in clinical research.

Quantification of prochlorperazine maleate in human plasma by liquid chromatography-mass spectrometry: Application to a bioequivalence study.

A sensitive and specific method using a one-step liquid-liquid extraction with dichloromethane followed by liquid chromatographic-electrospray ionization-mass spectrometric was developed and validated to determine prochlorperazine maleate in human plasma using amitriptyline hydrochloride as an internal standard. The samples were separated using a Thermo Hypersil-Hypurity C18 reversed-phase column (150mmx2.1mm i.d., 5mum). A mobile phase containing 10mM ammonium acetate (pH 3.6)-methanol-acetonitrile (27:68:5, v/v/v) was used isocratically eluting at a flow rate of 0.22ml/min. The average extraction recovery of prochlorperazine and internal standard were 81.8+/-2.2% and 79.5+/-3.7%, respectively. Prochlorperazine maleate and internal standard were measured by electrospray ion source in positive selective ion monitoring mode. The method demonstrated that good linearity ranged from 0.20 to 6.40ng/ml with r(2)=0.9989. The limit of quantification for prochlorperazine maleate in the plasma was 0.20ng/ml. The established method has been successfully applied to a bioequivalence study of two prochlorperazine maleate formulations in 18 healthy male Chinese volunteers.

In vitro and in vivo characteristics of prochlorperazine oral disintegrating film.

Oral disintegrating film containing prochlorperazine, a dopamine D(2) receptor antagonist with anti-emetic property, was newly developed using microcrystalline cellulose, polyethlene glycol and hydroxypropylmethyl cellulose as the base materials. The uniformity of dosage units of the preparation was acceptable according to the criteria of JP15 or USP27. The film showed an excellent stability at least for 8 weeks when stored at 40 degrees C and 75% in humidity. The dissolution test revealed a rapid disintegration property, in which most of prochlorperazine dissolved within 2 min after insertion into the medium. Subsequently, rats were used to compare pharmacokinetic properties of the film preparation applied topically into the oral cavity with those of oral administration of prochlorperazine solution. None of the parameters, including T(max), C(max), area under curves, clearance and steady-state distribution volume was significantly different between oral disintegrating film and oral solution. These findings suggest that the present prochlorperazine-containing oral film is potentially useful to control emesis induced by anti-cancer agents or opioid analgesics in patients who limit the oral intake.

The pharmacokinetics and bioavailability of prochlorperazine delivered as a thermally generated aerosol in a single breath to volunteers.

A thermally generated aerosol (TGA) system can effect reliable delivery of excipient-free drug to alveoli, resulting in rapid systemic drug absorption. We developed a pharmacokinetic model of prochlorperazine, administered by inhalation and as a rapid intravenous infusion, and we determined absolute TGA bioavailability in eight healthy volunteers in this institutional review board-approved, two-period crossover study. After the drug was administered as either a 5-s intravenous infusion or a TGA single-breath inhalation, blood was collected at various times for up to 24 h. Plasma prochlorperazine concentrations were measured using liquid chromatography-tandem mass spectrometry. Inhalation and rapid intravenous administration produced similar plasma prochlorperazine concentration profiles. Intravenous and inhalation pharmacokinetics were well characterized by a simultaneous two-compartment model with multiple absorption delays. Prochlorperazine pharmacokinetic parameters were similar to those reported for single intravenous doses. The geometric mean bioavailability after TGA delivery was 1.10. The administration of prochlorperazine by inhalation resulted in pharmacokinetics similar to that seen after intravenous administration, in terms of speed, extent, and consistency of absorption.

Simultaneous quantitation of plasma doxorubicin and prochlorperazine content by high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed and tested for simultaneous extraction, elution and determination of doxorubicin and prochlorperazine content in human plasma samples. The procedure consists of extraction through a conditioned C18 solid-phase extraction cartridge, elution from a Spherisorb C8 reversed-phase column by an isocratic mobile phase (60% acetonitrile, 15% methanol and 25% buffer) followed by detection with electrochemical and fluorescence detectors. Recovery of doxorubicin and prochlorperazine from pooled human plasma samples (n=3) containing 100 ng/ml of the two drugs was 77.8+/-3.5% and 89.1+/-6.0%, respectively. The lower limits of quantitation for doxorubicin and prochlorperazine in plasma samples were 6.25 ng/ml and 10 ng/ml, respectively. A linear calibration curve was obtained for up to 2 microg/ml of doxorubicin and prochlorperazine. This combination method may be of particular value in clinical studies where phenothiazines such as prochlorperazine are used to enhance retention of doxorubicin in drug resistant tumor cells.

Preliminary studies of the pharmacokinetics and pharmacodynamics of prochlorperazine in healthy volunteers.

The pharmacokinetics and pharmacodynamics of prochlorperazine were studied in healthy volunteers using a recently developed h.p.l.c. assay. Eight subjects received 12.5 mg and 6.25 mg i.v. doses of prochlorperazine, a 25 mg oral dose and placebo in random order. Plasma half-life (t1/2) of prochlorperazine was 6.8 +/- 0.7 h and 6.9 +/- 0.8 h for the 12.5 mg and 6.25 mg i.v. doses respectively. Apparent volume of distribution and plasma clearance were high and the kinetics did not appear to be dose-related. Absorption of oral prochlorperazine appeared to be slow and bioavailability was very low. A metabolite, possibly prochlorperazine sulphoxide, was noted after oral dosing. Mild sedation was common after i.v. prochlorperazine, but cardiovascular effects were minimal. The main adverse effect was akathisia which was reported by five out of eight subjects after the higher i.v. dose. These results provide preliminary information on the pharmacokinetics of i.v. prochlorperazine which were previously unknown.

Subnanogram quantitation of chlorpromazine in plasma by high-performance liquid chromatography with electrochemical detection.

A specific and sensitive high-performance liquid chromatographic (HPLC) method for the quantitative determination of subnanogram levels of chlorpromazine in plasma is described. Following extraction of chlorpromazine and the internal standard, prochlorperazine, HPLC analysis is carried out on a cyano column with a mobile phase consisting of 0.1 M ammonium acetate in acetonitrile (10:90 v/v). The use of oxidative thin-layer amperometric detection allowed the quantitation of 0.25 ng of chlorpromazine/ml of plasma with a coefficient of variation of 5.1%. The HPLC method has adequate sensitivity to follow plasma concentration-time profiles up to 24 hr following low single oral doses of chlorpromazine in healthy volunteers.

Radioimmunoassay for prochlorperazine in human plasma.

A new sensitive, specific, and rapid radioimmunoassay procedure for the determination of plasma concentrations of the antiemetic drug prochlorperazine is described. The assay enables the quantitation of 31 pg of the drug in 200 microliters of plasma with a coefficient of variation of approximately 2%. Except for N-desmethylprochlorperazine, the antiserum did not cross-react with the available metabolites tested. Also there was no cross-reactivity with the tricyclic antidepressants and antianxiety agents commonly co-administered with the drug. The method is suitable for single-dose pharmacokinetic and bioavailability studies. It should be adequate for the therapeutic monitoring of the drug in patients.