Bioequivalence study of domperidone dry suspension in healthy Chinese subjects under fasted and fed conditions: An open-label, randomized, single-dose, crossover trial.

BACKGROUND: Domperidone has long been used as a prokinetic agent in the treatment of epigastric distress symptoms. This study aimed to provide adequate evidence for registration approval of a new generic dry suspension formulation of domperidone by comparing the safety and pharmacokinetic profiles between the test and branded reference formulation in the context of fasted and fed condition. MATERIALS AND METHODS: This was designed as a randomized, open-label, single-dose, two-period, two-treatment crossover study. 32 and 28 eligible healthy subjects were enrolled in the fasted and fed study, respectively. Each subject was randomly assigned to receive either the test or reference formulation in the first period, followed by a 1-week washout period and dosing of the alternate formulation in the second period. A series of blood samples were collected at scheduled timepoints within 48 hours after administration during each treatment period. Plasma concentrations of domperidone were determined by validated HPLC-MS/MS. Pharmacokinetic parameters, including Cmax, tmax, AUC0-t, AUC0-∞, and T1/2, were acquired based on the concentration vs. time profiles by non-compartmental analysis using WinNonlin software. Then the geometric mean ratios (GMR) of Cmax, AUC0-t, and AUC0-∞ between the two formulations and corresponding 90% confidence intervals (CIs) were calculated for bioequivalence determination. Safety was assessed as routine. RESULTS: The two formulations showed similar pharmacokinetic profiles. Under fasted condition, the GMR and corresponding 90% CIs of AUC0-t, AUC0-∞, and Cmax were 101.48% (96.79 - 106.38%), 101.17% (96.66 - 105.90%), and 104.61% (96.73 - 113.14%), respectively. Under fed condition, the GMR and corresponding 90% CIs were 105.46% (99.19 - 112.12%), 104.21% (98.19 - 110.61%), and 112.78% (103.64 - 122.73%), respectively, for AUC0-t, AUC0-∞, and Cmax. All values fell within the accepted bioequivalence range of 80 - 125%. Both the test and the reference products were well tolerated without any serious or unexpected adverse reactions. CONCLUSION: Pharmacokinetic bioequivalence was established between the two dry suspension formulations of domperidone in healthy Chinese subjects. Both products were safe and well tolerated.

Piperine phytosomes for bioavailability enhancement of domperidone.

The markedly low oral bioavailability of domperidone (anti-emetic drug) is associated with rapid first-pass metabolism in the intestine and liver. To counteract such affects, there is a need to devise a strategy to enhance absorption and subsequently bioavailability. Thus, the current study was aimed at synthesizing phytosomes consisting of phosphatidylcholine and piperine (a P-glycoprotein inhibitor). Phytosomes were prepared by salting-out method. The developed phytosomes were extensively characterized for size, zeta potential, polydispersity index, entrapment efficiency (EE %), infra-red spectroscopy, X-ray diffraction, in vitro drug release, ex vivo permeation, in vivo pharmacokinetic and toxicity. The engineered formulations of phytosomes with piperine exhibited a significant improvement in oral bioavailability of domperidone (79.5%) in comparison with the pure drug suspension under the same conditions. Pharmacokinetic parameters such as maximal plasma concentration (Cmax) and the plasma concentration (estimated from area under the curve; AUC) of domperidone have been greatly increased relative to drug alone. The improved drug absorption was attributed to inhibition of P-glycoprotein transporter. The findings of current research work suggest that the optimized phytosomes based drug delivery containing phytochemicals as bioenhancers have the potential to improve bioavailability of poorly bioavailable drugs that are substrate to P-glycoprotein.

Pharmacomagnetography to evaluate the performance of magnetic enteric-coated tablets in the human gastrointestinal tract.

A magnetic enteric-coated tablet containing diclofenac sodium was produced, and its performance under physiological and disturbed gastrointestinal motility was assessed through pharmacomagnetography analysis. In vitro studies were performed using conventional methods and in vivo studies were conducted on healthy volunteers before (control) and after domperidone administration. The magnetic tablet's gastrointestinal (GI) transit and disintegration process were monitored using the Alternating Current Biosusceptometry sensors combined with drug plasmatic concentration. The Gastric Residence Time, Colon Arrival Time, Small Bowel Transit Time, Disintegration Time and the pharmacokinetics parameters were calculated. The pH-dependent polymers used to coat the magnetic tablets were able to avoid the premature drug release on gastric or small intestine simulated medium. Gastric Residence Time was accelerated compared with the control group (p < 0.01). No significant differences were found regarding small bowel transit, colon arrival, disintegration process, or pharmacokinetics parameters. A strong correlation between magnetic monitoring and pharmacokinetics parameters analysis was determinant to evaluate the efficiency in the drug delivery at a specific site in the human gastrointestinal tract. In addition, a tablet with a damaged coating was used as a proof of concept to show the suitability of our methodology to evaluate the tablet. Our study showed that pharmacomagnetography is a multi-instrumental approach towards assessing drug delivery and bioavailability.

Development of a sensitive UPLC-MS/MS assay for domperidone and pharmacokinetics of domperidone tablet formulations in fasting and fed Chinese healthy subjects
.

OBJECTIVE: The objective of this study was to evaluate and compare the pharmacokinetics of domperidone tablets in Chinese healthy subjects both under fasting and fed conditions. MATERIALS AND METHODS: A total of 36 subjects were recruited to the monocentric pharmacokinetic study. All subjects were randomly divided into two groups. One group was given a single 10-mg oral dose of domperidone tablet after ~ 10 hours of fasting, and the other group was given the same oral dose of domperidone tablet 30 minutes after a high-fat meal. 18 blood samples were collected over 24 hours for every subject. Plasma concentrations of domperidone were analyzed by a rapid and sensitive UPLC-MS/MS assay, and the pharmacokinetic parameters were determined by the standard non-compartmental method. RESULTS: A significant difference was observed in the pharmacokinetics of domperidone between fasting and fed subjects. The AUC0-24h (area under curve of plasma concentration until the last concentration observed) was 75.71 h×µg/L in the fed subjects, which was much higher than AUC0-24h (56.76 h×µg/L) in the fasting subjects. For the fasting test, the T1/2 (elimination half-life) was 7.15 hours, Cmax (the maximum plasma concentration) was 16.97 µg/L, and tmax; was 0.79 hours. For the fed test, the T1/2 was 8.72 hours, Cmax was 15.11 µg/L, and tmax was 1.66 hours. T1/2 and tmax were both prolonged under fed condition when comparing fed condition to fasting condition. CONCLUSION: In this study, the absorption and elimination of domperidone was slowed down by a high-fat meal, with the mean tmax being 52% longer and T1/2 18% longer in fed subjects than in fasting subjects. In addition, a high-fat meal increased the exposure of domperidone, with the mean AUC being 25% more in fed subjects than in fasting subjects, which provided an important reference for the clinical application of domperidone in the Chinese population.

Effects of Domperidone in Increasing Milk Production in Mothers with Insufficient Lactation for Infants in the Neonatal Intensive Care Unit.

Breast milk is the optimum for all infants, but hospitalization in the neonatal intensive care unit can cause separation of mothers and infants, which often interferes with milk secretion. Some reports show that domperidone is effective in promoting milk secretion. However, the Food and Drug Administration in the United States cautioned to not use domperidone for increasing milk volume because domperidone carries some risk of cardiac events, including QT prolongation, cardiac arrest, and sudden death. In contrast, it is used in Canada, Australia, and the United Kingdom with safety. The pharmacodynamics and pharmacokinetics of drugs may vary by race or ethnic origin, and it is not known whether domperidone is effective or safe for Japanese. In this study we report the effects of domperidone for Japanese mothers with insufficient lactation. Ten mothers were enrolled in a pilot study. After confirming that there were no abnormal findings on the electrocardiogram, the mothers were administered domperidone. Seven of 10 who took domperidone increased their milking volume. Prolactin was increased in 9 of 10 mothers. Adverse events were observed in two mothers, one headache and one abdominal pain; all symptoms were mild and improved promptly; and there were no adverse cardiac events. These results are consistent with reports from other countries. Domperidone may tentatively be considered effective for increasing milk secretion in Japanese mothers as in other populations. Our preliminary study of 10 cases indicates the need for further studies with larger sample sizes to assess the efficacy and safety of domperidone.

Endoscopic removal of a gastric pharmacobezoar induced by clomipramine, lorazepam, and domperidone overdose: a case report.

INTRODUCTION: Gastric pharmacobezoars are a rare entity that can induce mechanical gastric outlet obstructions and sometimes prolong toxic pharmacological effects. Certain medications, such as sustained-release forms, contain cellulose derivatives that may contribute to the adhesion between pills and lead to the creation of an aggregate resulting in a pharmacobezoar. Case reports are rare, and official guidelines are needed to help medical teams choose proper treatment options. CASE PRESENTATION: Our patient was a 40-year-old Caucasian woman with borderline personality disorder and active suicidal thoughts who was found unconscious after a massive drug consumption of slow-release clomipramine, lorazepam, and domperidone. On her arrival in the emergency room, endotracheal intubation was preformed to protect her airway, and a chest x-ray revealed multiple coffee grain-sized opaque masses in the stomach. She was treated with activated charcoal followed by two endoscopic gastric decontaminations 12 h apart in order to extract a massive gastric pharmacobezoar by manual removal of the tablets. CONCLUSION: This case demonstrates that in the case of a massive drug consumption, a pharmacobezoar should be suspected, particularly when cellulose-coated pills are ingested. Severe poisoning due to delayed drug release from the gastric aggregate is a potential complication. Detection by x-ray is crucial, and treatment is centered on removal of the aggregate. The technique of decontamination varies among experts, and no formal recommendations exist to date. It seems reasonable that endoscopic evaluation should be performed in order to determine the appropriate technique of decontamination. Care should be patient-oriented and take into account the clinical presentation and any organ failure, and it should not be determined solely by the suspected medication ingested. Thus, serum levels are not sufficient to guide management of tricyclic antidepressant intoxication.

Fused Deposition Modeling (FDM) 3D Printed Tablets for Intragastric Floating Delivery of Domperidone.

The aim of this study was to explore the feasibility of fused deposition modeling (FDM) 3D printing to prepare intragastric floating sustained release (FSR) tablets. Domperidone (DOM), an insoluble weak base, was chosen as a model drug to investigate the potential of FSR in increasing its oral bioavailability and reducing its administration frequency. DOM was successfully loaded into hydroxypropyl cellulose (HPC) filaments using hot melt extrusion (HME). The filaments were then printed into hollow structured tablets through changing the shell numbers and the infill percentages. Physical characterization results indicated that the majority of DOM gradually turned into the amorphous form during the fabrication process. The optimized formulation (contain 10% DOM, with 2 shells and 0% infill) exhibited the sustained release characteristic and was able to float for about 10 h in vitro. Radiographic images showed that the BaSO4-labeled tablets were retained in the stomach of rabbits for more than 8 h. Furthermore, pharmacokinetic studies showed the relative bioavailability of the FSR tablets compared with reference commercial tablets was 222.49 ± 62.85%. All the results showed that FDM based 3D printing might be a promising way to fabricate hollow tablets for the purpose of intragastric floating drug delivery.

Enhanced Oral Bioavailability of Domperidone with Piperine in Male Wistar Rats: Involvement of CYP3A1 and P-gp Inhibition.

PURPOSE: Domperidone is a commonly used antiemetic drug. The oral bioavailability of domperidone is very low due to its rapid first pass metabolism in the intestine and liver. Piperine, the main alkaloid present in black pepper has been reported to show inhibitory effects on Cytochrome P-450 (CYP-450) enzymes and P-glycoprotein (P-gp). In the present study we investigated the effect of piperine pretreatment on the intestinal transport and oral bioavailability of domperidone in male Wistar rats. METHODS: The intestinal transport of domperidone was evaluated by an in-vitro non-everted sac method and in-situ single pass intestinal perfusion (SPIP) study. The oral pharmacokinetics of domperidone was evaluated by conducting oral bioavailability study in rats. RESULTS: A statistically significant improvement in apparent permeability (Papp) was observed in rats pretreated with piperine compared to the respective control group. The effective permeability (Peff) of domperidone was increased in the ileum of the piperine treated group. Following pretreatment with piperine, the peak plasma concentration (Cmax) and area under the concentration- time curve (AUC) were significantly increased. A significant decrease in time to reach maximum plasma concentration (Tmax), clearance and elimination rate constant (Kel) was observed in rats pretreated with piperine. CONCLUSIONS: Piperine enhanced the oral bioavailability of domperidone by inhibiting CYP3A1 and P-gp in rats. This observation suggests the possibility that the combination of piperine with other CYP3A4 and P-gp dual substrates may also improve bioavailability. Further clinical studies are recommended to verify this drug interaction in human volunteers and patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose.

Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors. Because these recent clinical findings may indicate an important exception to the general rule that all antipsychotics interfere with dopamine at dopamine D2 receptors, the present study examined whether cannabidiol acted directly on D2 receptors, using tritiated domperidone to label rat brain striatal D2 receptors. It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole. The clinical doses of cannabidiol are sufficient to occupy the functional D2High sites. it is concluded that the dopamine partial agonist action of cannabidiol may account for its clinical antipsychotic effects.

Development, optimization and in vivo characterization of domperidone-controlled release hot-melt-extruded films for buccal delivery.

OBJECTIVE: The aim of the present investigation was the development and in vivo characterization of domperidone (DOM) hot-melt extruded (HME) controlled release films by central composite design (CCD) for buccal delivery. METHODS: Concentration of PEO N750 (X1) and HPMC E5 LV (X2) as independent variables and tensile strength (Y1), percent drug release at 6 h (Q6, Y2) and percent drug permeated at 6 h (Y3, P6) as responses. In total, 13 formulations were prepared and studied. HME films were evaluated for drug excipient compatibility, physico-mechanical properties, drug content, in vitro drug release, bioadhesion, swelling and erosion, ex vivo permeation. Furthermore, statistically optimized formulation was subjected for bioavailability studies in healthy human volunteers. RESULTS: Statistically optimized formulation exhibited a tensile strength (3.86 kg/mm(2)), 93.62 ± 2.84% of drug release and 63.36 ± 2.12% of drug permeated in 6 h. HME films demonstrated no drug excipient interaction and excellent content uniformity. Furthermore, optimized formulation exhibited elongation at break (38.6% mm(2)), peak detachment force (1.75 N), work of adhesion (3.21 mJ), swelling index (240.4%) and erosion (8.5%). Bioavailability from the statistically optimized buccal films was 3.2 times higher than the oral dosage form (p < 0.05). The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. The stability of the optimized formulation was studied and no significant changes were detected in 6 months. CONCLUSION: The results indicate that hot-melt extrusion is a viable technique for the preparation of DOM buccal-adhesive controlled release films with improved bioavailability by CCD.

A physiologically based pharmacokinetic modeling approach to predict drug-drug interactions between domperidone and inhibitors of CYP3A4.

Domperidone is a dopamine receptor antagonist and a substrate of CYP3A4, hence there is a potential for CYP3A inhibition-based drug-drug interactions (DDI). A physiologically based pharmacokinetic model was developed to describe DDIs between domperidone and three different inhibitors of CYP3A4. Simcyp V13.1 was used to simulate human domperidone pharmacokinetics and DDIs. Inputs included domperidone chemical and physical properties (LogP, pKa, etc.), in vitro human liver microsomal data and pharmacokinetic parameters from single-dose intravenous clinical studies in healthy participants. The simulated mean maximum domperidone plasma concentration and AUC after single- and multiple-oral doses under diverse conditions were within 1.1-1.4 fold of the observed values. The simulated intestinal availability, hepatic availability and the fraction absorbed were 0.45 ± 0.14, 0.31 ± 0.10 and 0.89 ± 0.11, respectively, and comparable to observed in vivo values. The simulated ratios of AUC and C(max) in the presence of ketoconazole, erythromycin or itraconazole to baseline were consistent with the observed ratios. Simulated ketoconazole, erythromycin, itraconazole and C(max,ss) and AUC(ss) were within 1.5-fold of the observed values.

QUINIDINE AND DOMPERIDONE INTERACTIONS IN THE RAT EXPERIMENTAL MODEL OF REPEATED ADMINISTRATION.

This study has investigated domperidone (DOM) and quinidine (QD) interaction in the Wistar rat experimental model of repeated administration. We used nonconventional administration model consistent with occasional administration method. Difference in administration was related to sequence of domperidone alone or with quinidine dosage. Expected domperidone-quinidine interactions could have its origin both in the ability of quinidine to inhibit P-glycoprotein (P-gp) activity as well as cytochrome P450-mediated metabolism of both compounds. There also were examined kinetics of acetaminophen (PAM) administered (30 mg/kg) with domperidone as an indicator of gastric emptying, showing domperidone prokinetic activity, as well as quinidine anticholinergic activity. Domperidone (30 mg/kg) with PAM and with/without quinidine (25 mg/kg) was administered orally according to the disposition regiment different for six examined rat groups. DOM and PAM concentrations in plasma were assayed by HPLC method. Following changes were observed: domperidone did not modify the duration of the uptake phase of acetaminophen; quinidine prolongs gastric emptying time (as a result of anticholinergic action); quinidine given as the fourth or fifth dose with domperidone promotes growth of its concentration in plasma; analysis of changes in the value of AUC(0-2) at the initial three weeks of experiment suggests intensity of domperidone absorption processes, the following week increase in the value AUC(4-6) suggests inhibition of domperidone hepatic biotransformation and the mechanism of induction of absorption during domperidone administration is different from the absorption - inducing effects of quinidine. Both effects are superimposed and produce large, 2, 3-fold change in domperidone's AUC(0-6).

Effect of rifampicin pretreatment on the oral bioavailability of domperidone in healthy human volunteers.

BACKGROUND: Increased exsorption of domperidone was observed from different parts of the small intestine of the rat after pretreatment with rifampicin by the everted sac method. Based on the in vitro studies the effect of rifampicin pretreatment on the pharmacokinetics of domperidone was investigated in eight healthy male volunteers. METHODS: After an overnight fast, 20 mg domperidone was administered to the volunteers, either alone or after 6 days pretreatment with a once daily dose of 600 mg rifampicin. Serum concentrations of domperidone were estimated by reverse phase HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program kinetica. RESULTS: Rifampicin pretreatment decreased Cmax, AUCo-∞, AUMC, MRT and t1/2 by 25.11%, 37.76%, 64.97%, 43.71% and 44.48%, respectively. This may be due to increased induction of cytochrome P450 enzymes and/or increased expression of P-glycoprotein. CONCLUSIONS: This interaction may have clinical significance when domperidone is co-administered with rifampicin in chronic treatment conditions, such as tuberculosis, leprosy and other infections of joints, bones, etc.

Design and Optimization of Domperidone Fast Dissolving Tablet Using Central Composite Design.

The main aim present work was to optimize fast dissolving tablet (FDT) formulation using response surface approach. The variables studied were sodium bicarbonate (X1), citric acid (X2), and superdisintegrant, Ac-Di-Sol (X3). The main aspect of present work was to develop FDT of Domperidone which possesses fast disintegration and high mechanical strength. It was found that the response was affected by all the three factors studied. The statistical models were successfully used to prepare FDT of Domperidone with fast disintegration (31.08 seconds) and adequate hardness (4.1 kg/cm(2)). Pharmacokinetic studies in rats showed statistically insignificant difference (p>0.05) between Domperidone fast dissolving tablet (DFDT) and market product. This concluded that optimized FDT is bioequivalent with the marketed formulation. The values of Tmax were found to be 0.5 h and 0.75 h for DFDT and reference product, respectively. Conditioned place aversion study was performed on Swiss Albino mice and the study showed the better anti emetic potency of optimized FDT in nauseated condition over market product (p<0.05). Thus, the present investigation conclusively demonstrates the potential role in terms of rapid disintegration and high mechanical strength.

[Proarrhythmic effects of domperidone in infants: a systematic review]. / Revisión Sistemática de la evidencia de efectos proarrítmicos de domperidona en infantes.

AIMS: To assess the association of the use of domperidone in infants with QTc interval prolongation and proarrhythmic events. METHODS: A systematic search of the scientific literature was conducted without any date or language restriction. The electronic database MEDLINE and the sources LILACS, ScIELO and Cochrane library were consulted. RESULTS: From the twelve identified studies, eight were excluded because they did not meet the inclusion criteria. One case report and three pilot studies were selected. Rocha et al (2005) reported the case of an infant (age 3 months) with QTc interval = 463 ms after being treated during one month with 1.8 mg/kg/day of oral domperidone. Djeddi et al (2008) administered an average dose of 1.3 mg/kg/day to 31 neonates; QTc interval prolongation > 30 ms was observed in nine neonates. Hegar et al (2009) studied 10 infants (mean age 5.6 months) who received 0.8 mg/ kg/day of oral domperidone; QTc interval prolongation was not observed. Günlemez et al (2010) enrolled 40 premature infants who were administered 1 mg/kg/day of oral domperidone; the QTc interval increased to above 450 ms in two infants. CONCLUSIONS: Although evidence that orally administrated domperidone in infants produces prolongation of QTc interval was found, further studies are needed in order to quantify the risk associated with the drug in that population. We suggest that heath professionals should conduct ECGs to infants treated with domperidone and inform the pharmacovigilance system the occurrence of any case of adverse event.

Objetivo: Determinar si existe evidencia de prolongación del intervalo QTc y efectos proarrítmicos asociados al uso de domperidona oral en infantes. Método: Se realizó una revisión sistemática de la literatura científica consultando la base de datos electrónica MEDLINE y las fuentes LILACS, ScIELO y Biblioteca Cochrane a través de la Biblioteca Virtual de Salud, sin límite de fecha ni de idioma. Resultados: De los estudios identificados se excluyeron ocho por no cumplir con los criterios de inclusión, quedando seleccionados un reporte de caso y tres estudios pilotos. Rocha et al (2005) reportan el caso de un niño de 3 meses con intervalo QTc=463 mseg tras un mes de tratamiento con 1,8 mg/kg/día de domperidona oral. Djeddi et al (2008) administraron una dosis promedio de 1,3 mg/kg/día a 31 neonatos, observando prolongación del intervalo QTc>30 mseg en nueve. Hegar et al (2009) estudiaron a 10 niños con edad media de 5,6 meses tratados con 0,8 mg/kg/día y no observaron prolongación del intervalo QTc. Gunlemez et al (2010) incluyeron en su estudio a 40 infantes prematuros a quienes administraron 1 mg/kg/día de domperidona oral, en dos de ellos el intervalo QTc aumentó por encima de 450 mseg. Conclusiones: Aunque se encontró evidencia de prolongación del intervalo QTc en infantes tratados con domperidona oral, se necesitan más estudios para cuantificar el riesgo asociado a la droga en esta población. Se sugiere a los profesionales de la salud realizar un monitoreo electrocardiográfico de los infantes tratados con domperidona e informar al sistema de farmacovigilancia los casos de ocurrencia de eventos adversos.

Current use of domperidone and co-prescribing of medications that increase its arrhythmogenic potential among older adults: a population-based cohort study in Ontario, Canada.

BACKGROUND AND OBJECTIVES: Domperidone is commonly used to treat nausea and gastrointestinal disorders. Recent data suggests that it may increase the risk of sudden cardiac death, particularly in older people. Little is known about how it is used in contemporary practice. This study sought to characterize the population of older adults newly dispensed domperidone, describe dosages of domperidone used, and determine the frequency of co-prescribing domperidone with medications that may increase the arrhythmogenic potential of domperidone. METHODS: This is a retrospective cohort study using administrative health database information from Ontario, Canada. Prescription medication records were obtained from the Ontario Drug Benefit Claims Database. Diagnostic codes were obtained from the Ontario Health Insurance Plan Database, the Canadian Institute for Health Information Discharge Abstract Database, and the same-day surgery database. Patients who received a new prescription for domperidone between April 1, 2003 and March 31, 2010 were included. RESULTS: A total of 122,233 patients met inclusion criteria; 85 % were between 66 and 84 years old and 63 % were female. The mean estimated daily domperidone dose was 35 mg, and the estimated daily dose was <40 mg for 62 % of users. Strong or moderately strong cytochrome P-450 (CYP) 3A4 inhibitors were co-prescribed for 4.3 and 10.7 % of users, while medications with a known risk or possible risk for torsades de pointes (TdP) were co-prescribed to 18.3 and 18.8 % of users. CONCLUSIONS: Older domperidone users were commonly co-prescribed drugs with the potential to increase the risk for TdP. These combinations should be avoided, as iatrogenic QT prolongation is a modifiable risk factor for TdP.

Determination of domperidone in human plasma using high performance liquid chromatography with fluorescence detection for clinical application.

A simple and reliable method for the determination of domperidone in human plasma has been developed. Plasma samples (1mL) were pre-purified by a solid-phase extraction with Bond Elut(®) C18. The separation was achieved with XBridge™ C18 column (150mm×4.6mm i.d., 5µm) at 40°C. The mobile phase was a mixture of acetonitrile and 10mM ammonium acetate buffer (36:64, v/v), adjusted to pH 9.4 with 20% ammonium solution at a flow rate of 1.0mL/min. The peak was detected using fluorescence detector at excitation 282nm and emission 328nm. Retention times for domperidone and internal standard (propranolol) were 8.3min and 11.2min, respectively. The method showed a good linearity (r>0.999), precision (relative standard deviations <10.6%), and extraction recovery (85.7-99.7%) over a concentration of 1-100ng/mL. The lower limit of quantification (LLOQ) was 1.0ng/mL. This proposed method was successfully applied to a pharmacokinetic interaction study of domperidone in healthy Japanese volunteers.

Development and optimization of self microemulsifying drug delivery of domperidone

The present investigation is aimed to develop self-microemulsifying drug delivery system (SMEDDS) to improve the in vitro dissolution of a BCS (Biopharmaceutical Classification System) class II anti emetic agent, domperidone. Solubility study was performed to identify the ingredients showing highest solubility of domperidone. The ternary phase diagrams were plotted for selected components to identify the area of microemulsion existence. D-optimal mixture experimental design was applied to optimize a liquid SMEDDS using formulation variables; the oil phase X1 (Oleic acid), the surfactant X2 (Labrasol) and the co-surfactant X3 (Transcutol HP). The liquid SMEDDS were evaluated for droplet size, emulsification time, % transmittance and drug release. Stability study was performed at 40 °C/75% RH. Liquid formulation was solidified by adsorption on carrier Aerosil 300. Solid SMEDDS was evaluated and compared with liquid SMEDDS and marketed formulation. Oleic acid was selected as oil, Labrasol as surfactant and Transcutol HP as co-surfactant for formulation of SMEDDS. The optimized batch showed best results in terms of smaller droplet size (<170 nm), emulsification time (<40 s) and drug release (>85% in 15 min) and was stable for 3 months. Solid SMEDDS containing Aerosil 300 showed good flow properties and uniform drug content. XRPD study revealed that the crystalline drug was converted to amorphous form in solid SMEDDS. The rate and extent of drug dissolution from solid SMEDDS was significantly higher than pure drug and commercial tablet formulation. The results demonstrate the potential of SMEDDS as a means of improving solubility, dissolution and hence the bioavailability.

O presente estudo teve como objetivo desenvolver sistemas de liberação auto-microemulsificantes (Self-Microemulsifying Drug Delivery System - SMEDDS) de domperidona, agente antiemético, classe II, segundo o sistema de classificação Biofarmacêutica, para melhorar sua dissolução in vitro. Estudo foi realizado para identificar os componentes que revelaram maior solubilidade da domperidona. Determinaram-se os diagramas de fase ternários para esses componentes selecionados tendo em vista a identificação da região de formação da microemulsão. O planejamento experimental foi empregado para otimizar os SMEDDS líquidos, utilizando as seguintes variáveis de formulação: a fase oleosa X1 (ácido oleico), o agente tensoativo X2 (Labrasol) e co-tensoativo X3 (Transcutol HP). Os SMEDDS líquidos foram avaliados quanto às seguintes características: tamanho da gota, tempo de emulsificação,% de transmitância e liberação do fármaco. O estudo de estabilidade foi realizado a 40 °C/75% de umidade relativa. A formulação foi convertida em forma sólida por sua adsorção em Aerosil 300. Os SMEDDS sólidos foram avaliados e comparados com SMEDDS líquidos e a formulação comercializada. O ácido oléico foi selecionado para a fase oleosa, Labrasol como agente tensoativo e Transcutol como co-tensoativo para a formulação de SMEDDS. O lote otimizado mostrou os melhores resultados: menor tamanho de gota (<170 nm), menor tempo de emulsificação (<40 segundos), e de liberação do fármaco (> 85% em 15 min). Além disso, a formulação otimizada manteve-se estável no período de 3 meses. Os SMEDDS sólidos contendo Aerosil 300 apresentaram boas propriedades de fluxo e uniformidade de conteúdo do fármaco. O estudo de difração de raios-X revelou que o fármaco cristalino foi convertido para a forma amorfa, nos SMEDDS sólidos. A velocidade de dissolução do fármaco a partir dos SMEDDS sólidos foi significativamente maior, quando comparado ao fármaco livre e à formulação de comprimidos comercial. Os resultados demonstram o potencial dos SMEDDS como meio para melhorar a solubilidade, a dissolução e, consequentemente, a biodisponibilidade da domperidona.

Rapid and sensitive UPLC-MS/MS method for the determination of domperidone in human plasma and its application to pharmacokinetic study.

In this study, a simple, rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method is described for determination of domperidone in human plasma samples using oxcarbazepine as the internal standard (IS). Sample preparation was accomplished through protein precipitation with methanol, and chromatographic separation was performed on an Acquity BEH C18 column (2.1 mm×50 mm, 1.7 µm) with gradient profile at a flow of 0.45 mL/min. Mass spectrometric analysis was performed using a QTrap5500 mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transition of m/z 426.3→175.2 was used to quantify for domperidone. The linearity of this method was found to be within the concentration range of 0.25-100.0 ng/mL for domperidone in human plasma. Only 1.5 min was needed for an analytical run. The method herein described was superior to previous methods and was successfully applied to the pharmacokinetic study of domperidone in healthy Chinese volunteers after oral administration.

Effect of piperine, a major component of black pepper, on the pharmacokinetics of domperidone in rats.

The present study was aimed to investigate the effect of piperine, a major active ingredient of black pepper, on the pharmacokinetics of domperidone in rats. Animals were given oral (p.o.) or intraperitoneal (i.p.) domperidone (20 mg/kg) alone or together with piperine (20 mg/kg, p.o.). Plasma samples were collected at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0 and 12 hours after drug administration. The concentration of domperidone in the plasma was measured using a HPLC method. The concomitant administration of piperine with oral or intraperitoneal domperidone resulted in a significant (P<0.05) increase in the maximum plasma concentration (Cmax), the mean area under the plasma concentration-time curve (AUC), and the elimination half-life (t1/2) of domperidone as compared to those obtained for domperidone alone. These results suggest that an important pharmacokinetic interaction may occur if piperine is administered concurrently with domperidone.