An HPLC-ESI-MS method for simultaneous determination of fourteen metabolites of promethazine and caffeine and its application to pharmacokinetic study of the combination therapy against motion sickness.

The combination therapy, promethazine and caffeine had been proven effective in treating motion sickness and counteracting some possible side effects of using promethazine alone while the mechanism and interaction remained unclear. Therefore, an HPLC-ESI-MS method for simultaneous determination of both drugs, and their metabolites was developed for purpose of pharmacokinetic study. To determine as many metabolites as possible, the influence of parameters such as column, flow rate and pH value of mobile phase, ionization polarity and fragmentation voltage were optimized. Fourteen target analytes were well separated and all of them could be identified and determined in plasma after administration of promethazine and caffeine. The LODs and LOQs were 0.9-6.0 and 2.50-16.0 ng/ml, respectively; the recoveries of three levels of quality control samples were from 86.7% to 102%; the intra-day and inter-day precisions were less than 3% and 9%, separately; and the RSDs of compound stability were all lower than 10% within 24h after sample preparation. As a pharmacokinetic study of the combination therapy in 30 healthy volunteers, concentration-time curves of the drugs and metabolites were studied. The present method for simultaneous measurement of more than ten metabolites is valuable for the study of mechanism and interaction of the combination therapy.

Extended release promethazine HCl using acrylic polymers by freeze-drying and spray-drying techniques: formulation considerations / Liberação prolongada prometazina HCl utilizando polímeros acrílicos por liofilização e técnicas de secagem por aspersão: consideração de formulação

The present study investigated a novel extended release system of promethazine hydrochloride (PHC) with acrylic polymers Eudragit RL100 and Eudragit S100 in different weight ratios (1:1 and 1: 5), and in combination (0.5+1.5), using freeze-drying and spray-drying techniques. Solid dispersions were characterized by Fourier-transformed infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), Powder X-ray diffractometry (PXRD), Nuclear magnetic resonance (NMR), Scanning electron microscopy (SEM), as well as solubility and in vitro dissolution studies in 0.1 N HCl (pH 1.2), double-distilled water and phosphate buffer (pH 7.4). Adsorption tests from drug solution to solid polymers were also performed. A selected solid dispersion system was developed into capsule dosage form and evaluated for in vitro dissolution studies. The progressive disappearance of drug peaks in thermotropic profiles of spray-dried dispersions were related to increasing amount of polymers, while SEM studies suggested homogenous dispersion of drug in polymer. Eudragit RL100 had a greater adsorptive capacity than Eudragit S100, and thus its combination in (0.5+1.5) for S100 and RL 100 exhibited a higher dissolution rate with 97.14 percent drug release for twelve hours. Among different formulations, capsules prepared by combination of acrylic polymers using spray-drying (1:0.5 + 1.5) displayed extended release of drug for twelve hours with 96.87 percent release followed by zero order kinetics (r²= 0.9986).

O presente trabalho compreendeu estudo de um novo sistema de liberação prolongada de cloridrato de prometazina (PHC) com polímeros acrílicos Eudragit RL100 e Eudragit S100 em diferentes proporções em massa (1:1 e 1:5) e em combinação (0,5+1,5), utilizando técnicas de liofilização e de secagem por aspersão As dispersões sólidas foram caracterizadas por espectrofotometria no infravermelho por transformada de Fourier (FT-IR), calorimetria diferencial de varredura (DSC), difratometria de raios X (PXRD), Ressonância Magnética Nuclear (RMN), microscopia eletrônica de varredura (SEM) e, também, por estudos de solubilidade e de dissolução in vitro em HCl 0,1 N (pH 1,2), água bidestilada e tampão fosfato (pH 7,4). Realizaram-se, também, testes de adsorção da solução do fármaco nos polímeros sólidos. Desenvolveu-se sistema de dispersão sólida exclusiva dentro das cápsulas, que foi avaliado por meio de estudos de dissolução in vitro. Relacionou-se o desaparecimento progressivo de picos do fármaco em perfis termotrópicos de dispersões secas por spray à quantidade aumentada de polímero, enquanto os estudos de SEM sugeriram dispersão homogênea do fármaco no polímero. O Eudragit RL100 apresentou maior capacidade de adsorção do que o Eudragit S100 e, dessa forma, a combinação de (0,5+1,5) para S100 e para RL100 mostrou taxa de dissolução maior, com liberação de 94,17 por cento de fármaco em 12 horas. Entre as várias formulações, as cápsulas preparadas pela combinação de polímeros acrílicos utilizando secagem por aspersão (0,5+1,5) apresentou liberação prolongada do fármaco em 12 horas, com 96,78 por cento de liberação, seguindo cinética de ordem zero (r² = 0,9986).

Interaction of tomato lectin with ABC transporter in cancer cells: glycosylation confers functional conformation of P-gp.

Phospho-glycoprotein (P-gp) is a polytopic plasma membrane protein whose overexpression causes multidrug resistance (MDR) responsible for the failure of cancer chemotherapy. P-gp 170 is a member of the ATP-binding cassette (ABC) transporter superfamily and has two potentially interesting regions for drugs interfering with its efflux function, namely the oligosaccharides on the first extracellular loop with unknown function and the two intracellular ATP-binding regions providing the energy for drug efflux function. The polylactoseamine oligosaccharides on the first loop can specifically bind the tomato lectin (TL). The P-gp efflux activities of TL-pre-treated MDR resistant cells were measured in the presence of structurally unrelated resistance modifiers such as phenothiazines, terpenoids and carotenoids. The inhibition of efflux activity was measured via the increased rhodamine uptake by mouse lymphoma cells transfected in human MDR1 gene and in human brain capillary endothelial cells. The tested resistance modifiers inhibit the function of ABC transporter resulting in increased R123 accumulation in MDR1 expressing cells. TL prevented the inhibitory action of phenothiazine and verapamil on brain capillary endothelial and MDR1-lymphoma cells, presumably due to the stabilization of the functional active conformation of P-gp. Our results indicate that the polylactosamine chains of P-gp are part of the functionally active protein conformation.

Development and validation of a sensitive LC-MS method for the determination of promethazine hydrochloride in human plasma and urine.

We developed and validated a sensitive and low sample volume liquid chromatographic-mass spectrometric (LC-MS) method for determination of Promethazine hydrochloride in human plasma (0.5 ml) or urine (0.1 ml). The lower limit of quantification in human plasma and urine was 1.00 ng/ml. The inter- and intra-day precisions (CV %) in both plasma and urine were lower than 10%, the mean method accuracies and recoveries from spiked plasma samples at three concentrations were more than 97%. The developed method was successfully applied to determine Promethazine hydrochloride in human plasma and urine, and proved suitable to clinical pharmacokinetic study.

Development and validation of a sensitive LC-MS method for the determination of tramadol in human plasma and urine.

A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS) method was developed and validated for the determination of Tramadol in human plasma and urine. The analyte was separated on a Diamonsil C18 column with ammonium acetate (5 mmol x L(-1))-methanol (50:50,v:v) adjusted PH by caustic soda at a flow rate of 0.8 ml min(-1), and analyzed by mass spectrometry is in positive ion mode. The ion mass spectrum of m/z were 264.1 for Tramadol and 248.0 for Tinidazole (I.S.), respectively. The weighted (1/x2) calibration curve was linear over plasma concentration range 1.00-400.00 ng/ml and urine concentration range 0.01-16.00 microg/ml, with a correlation coefficient (r) of 0.9995 and 0.9997, respectively. The lower limit of quantification in human plasma was 1.00 ng/ml. The inter-and intra-day precisions (CV%) in both plasma and urine were lower than 10%, the mean method accuracies and recoveries from spiked plasma samples at three concentrations ranged from 98.2 to 100.1% and 61.6 to 62.9%, respectively. The developed method was successfully applied to determine Tramadol in human plasma and urine, and provided suitable profiles for clinical pharmacokinetic study of Tramadol.

Pharmacokinetics, safety and tolerance of single- and multiple-dose of a novel compound tramadol hydrochloride injection (35 mg tramadol hydrochloride, 45 mgl promethazine hydrochloride) in Chinese healthy subjects.

The pharmacokinetics of Tramadol and Promethazine after a single dose of 40, 80 and 120 mg intramuscular injecting CTHI was evaluated in healthy volunteers. Physical exam, vital signs, clinical laboratory tests and electrocardiogram measurements were monitored to assess the safety and tolerance of the drug. The plasma levels of Tramadol and Promethazine in serial samples were measured by a validated HPLC-MS method. No subject showed any drug-related clinically significant changes on physical examination, vital signs or laboratory tests.

Development of a melting tablet containing promethazine HCl against motion sickness.

The purpose of this study was to design a 'Traveller Friendly Drug Delivery System' for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granules by direct compression using Ac-Di-Sol, Polyplasdone-XL, Primojel and ion-exchanger Tulsion339 and evaluated for mass uniformity, friability, tensile strength, drug content uniformity, water absorption ratio, in-vitro and in-vivo disintegration time and in-vitro dissolution studies. The observed drug-polymer interactions and reduced crystallinity may be reasons for increased dissolution rates. The formulated tablets were disintegrated within 15 s. Tablets (25 mg PM-HCl) with Ac-Di-Sol (4%) showed complete release within 1 min, while marketed conventional tablets (Phenergan; Rhone-Poulec) release 25% during the same period. A preliminary stability studies for the prepared tablets carried at 30 +/- 2 degrees C/60 +/- 5% RH, and 40 +/- 2 degrees C/75 +/- 5%RH for 3 months showed no significant changes in the tablets quality at 30 +/- 2 degrees C/60 +/- 5% RH. However, at 40 +/- 2 degrees C/75 +/- 5%RH marked increase in in-vitro disintegration time, tensile strength and decrease in friability and water absorption ratio was found. The present studies indicate the abilities of Eudragit E 100 for taste masking and improving the dissolution profile of PM-HCl after complexation. In addition, by employing cost effective direct compression method, fast-dissolving tablets of 400 mg total weight with an acceptable quality could be prepared.

Complicated pain management in a CYP450 2D6 poor metabolizer.

We describe the case of a patient with significant adverse effects from posttraumatic analgesic therapy with opioid analgesics who was found by microarray analysis to have a CYP2D6 genotype predictive of a poor metabolizer phenotype. In addition to her poor tolerance and limited response to opioid analgesics, she developed further discomfort when the antiemetic promethazine was administered to treat her gastrointestinal adverse effects. In our discussion we review the literature about the clinical impact of CYP450 2D6 polymorphisms in treatment with the commonly used opioid analgesics codeine, oxycodone, hydrocodone, hydromorphone, and morphine, as well as the antiemetic promethazine. The case we present, as well as the literature we review, demonstrates the clinical utility of CYP2D6 genotyping in patients with adverse effects from analgesia therapy.

Influence of simulated weightlessness on the intramuscular and oral pharmacokinetics of promethazine in 12 human volunteers.

The National Aeronautics and Space Administration (NASA) recommends using promethazine to prevent and treat space motion sickness, but pharmacologic responses in space and on Earth are different. Twelve volunteers were given 50 mg promethazine orally or intramuscularly before and after 48 hours of bed rest to simulate weightlessness. The maximum measured plasma concentration (C(max)), time to C(max) (t(max)), and area under plasma concentration versus time curve from 0 to infinity (AUC(inf)) were determined, and the bioequivalence was tested between bed-rest and ambulatory status for the intramuscular and oral routes as well as between both routes for bed-rest and ambulatory position. Simulated weightlessness did not influence the ratio AUC(bed rest)/AUC(ambulatory) after intramuscular injection, whereas a significant increase (26%) in the ratio was seen after oral administration, probably because of a prolonged contact time between promethazine and the intestinal wall associated with an increase in the intestinal transit time. The AUC was 3-fold higher when the drug was administered by the intramuscular route during both positions. Thus, intramuscular administration could be a good alternative to the oral route.

Systematic delivery of chloroquine and promethazine using pH-sensitive polymers.

Two pH sensitive polymers (Eudragit L30 D55 and L100) were used as coating materials, respectively, for promethazine hydrochloride and chloroquine phosphate granules formulated with sodium carboxylmethylcellulose and Carbopol 940, respectively, in the ratios 1:1, 1:2, 1:3, and 1:4 (drug:polymer). The granules were characterized. Release studies for the uncoated and coated particles were studied in simulated gastric fluid and simulated intestinal fluid. Result obtained showed that 1:1 and 1:2 ratios of both coated and uncoated granules of the two drugs had short release times and could be recommended for rapid action, whereas 1:4 ratio with low release time could be used for sustained effect. The two granules could be used at varying ratios to obtain desired release characteristics, such that therapeutic concentrations of the two drugs could be achieved.

Interaction of surface-active drugs in rabbits.

The interaction of chlorpromazine and promethazine in vivo has been investigated. The drugs were administered to the rabbit orally as a single dose (100 mg of each drug) as well as simultaneously with an interval of 15 min. The presence of multiple peaks at the separate administration of promethazine and chlorpromazine on the one hand, and increase of number of peaks, symbathic character of kinetic curves of mentioned drugs and its prolonged appearance in the systemic circulation of the blood by simultaneous administration on the other hand, may be explained by the intensive presystem metabolism and surface-activity ability of these drugs, and by the periodic 'lassitude' of liver for their capture and elimination (either presystem or systemic). The micelle formation from these drugs in the gastro-intestinal tract and formation of the mixed micelles on simultaneous administration were also taken into consideration. Chlorpromazine is more strongly captured by the liver at its first pass through it than promethazine, from comparison of pharmacokinetics of these drugs administered separately. Therefore, chlorpromazine on simultaneous administration occupies the sites of the liver which were covered by promethazine at single dose, thereby substituting promethazine and promoting its transferral into the systemic blood circulation. This results in a large increase in promethazine content in blood, additional peaks appear and the presence of promethazine in the blood is prolonged. The influence of chlorpromazine on the kinetics of promethazine is especially obvious when chlorpromazine enters the organism first and more easily occupies those sites in the liver which participate in the capture and elimination of both drugs. Concerning influence of promethazine on the kinetics of chlorpromazine, promethazine reinforces in some way the ability of liver to capture chlorpromazine, thereby intensifying the presystem metabolism of chlorpromazine and inhibiting its own metabolism. The analogous effect was observed in the study of the influence of promethazine on the kinetics of carbamazepine.

The effects of acute doses of fexofenadine, promethazine, and placebo on cognitive and psychomotor function in healthy Japanese volunteers.

BACKGROUND: Genetic variations in cross-cultural metabolic capability may attenuate the lack of central nervous system effects of fexofenadine. OBJECTIVE: To compare the pharmacodynamics of fexofenadine and promethazine versus placebo in Japanese volunteers. METHODS: In this randomized, crossover, double-blind study, 24 subjects received single doses of fexofenadine 60 mg and 120 mg, promethazine 25 mg, and placebo, with a 6-day washout period between treatments. Objective measures included critical flicker fusion, choice reaction time, and a compensatory tracking task. A line analog rating scale evaluated self-rated sedation. A rapid visual information-processing task evaluated vigilance at baseline and at 2 hours. RESULTS: Fexofenadine was not significantly different from placebo on any test at any timepoint. In contrast, promethazine impaired critical flicker fusion thresholds (F[3,63] = 5.37, P = 0.0023); increased recognition reaction time (F[3,63] = 13.63, P < 0.0001) and total reaction time (F[3,63] = 12.23, P < 0.0001) components of the choice reaction time test; reduced tracking accuracy (F[3,63] = 14.25, P < 0.0001) and increased reaction times to peripheral stimuli (F[3,63] = 9.29, P < 0.0001) in the compensatory tracking task; reduced the number of valid responses (F[3,63] = 14.86, P < 0.0001) and impaired reaction times (F[3,63] = 12.02, P < 0.0001) in the rapid visual information-processing task test; and impaired subjective ratings of sedation (F[3,63] = 7.55, P = 0.0002), compared with placebo. CONCLUSIONS: A battery of tests sensitive to impairment by promethazine failed to show any negative cognitive or psychomotor effects with fexofenadine 60 and 120 mg. Fexofenadine is an intrinsically non-impairing antihistamine in Japanese subjects.

Interaction of carbamazepine and promethazine in rabbits.

The interaction of carbamazepine and promethazine in rabbits has been investigated. The influence of this interaction on the processes of biotransformation in the liver was revealed. The drugs were administered as single oral doses (100 mg of each drug) as well as simultaneously with an interval of 15 min. The sequence of administration of the drugs was varied. The influence of promethazine on the pharmacokinetics of carbamazepine is expressed by: (a) strong suppression of carbamazepine's level in plasma and appearance of multiple peaks of carbamazepine; (b) suppression of biotransformation of carbamazepine into carbamazepine-10,11-epoxide at the initial stages and its increase in the intermediate stages. These data are explained by the active capture of carbamazepine by liver at its primary transferal through the liver and sufficient presystem elimination of carbamazepine in the presence of promethazine. The character of kinetic curves of promethazine varies substantially under the influence of carbamazepine. However, this change is not as strong as in case of carbamazepine. The concentration of promethazine in plasma varies slightly and multiple peaks are not observed. The rate of terminal elimination of promethazine varies and abrupt prolonged segments of elimination appear at the initial and terminal stages of the process in return. These data perhaps indicate the induction of biotransformation of promethazine in the presence of carbamazepine-an inductor of microsomal liver enzymes. The changes of kinetics of promethazine and carbamazepine by simultaneous administration as compared with their administration separately, as well as a comparative consideration of pharmacokinetics of promethazine and carbamazepine by simultaneous administration show the existence of competition in the elimination between these drugs and the periodic saturation of liver for their biotransformation.

Investigation of interaction of promethazine with cyclodextrins.

The effect of beta-CD and its substituted derivatives (DM-beta-CD and HP-beta-CD) on the solubility and photostability of promethazine was investigated in solution and in the solid state. The soluble complexes of protonated (pH = 6.8) and basic (pH = 10.8) forms of promethazine with CDs were studied using the spectral method. The influence of pH and CD complexation on photostability of PM in solution was followed. It was found that the photochemical decomposition of promethazine (PM) alone and in the presence of CD proceeds according to the first order reaction. It was also established that as well the presence of CD as the acidic medium of reaction increased the photostability of PM in solution. Formation of solid inclusion complexes of PM with CDs was evaluated using FT IR, 13C NMR and DSC methods. The results obtained indicate that independently of the complexation method in the solid state (kneading or heating), the presence of CD decreases the solubility of PM; the reason may be that the phenothiazine ring of PM did not enter into the cavity of beta-CD and its derivatives.

Quantitation of promethazine and metabolites in urine samples using on-line solid-phase extraction and column-switching.

A chromatographic method for the quantitation of promethazine (PMZ) and its three metabolites in urine employing on-line solid-phase extraction and column-switching has been developed. The column-switching system described here uses an extraction column for the purification of PMZ and its metabolites from a urine matrix. The extraneous matrix interference was removed by flushing the extraction column with a gradient elution. The analytes of interest were then eluted onto an analytical column for further chromatographic separation using a mobile phase of greater solvent strength. This method is specific and sensitive with a range of 3.75-1400 ng/ml for PMZ and 2.5-1400 ng/ml for the metabolites promethazine sulfoxide, monodesmethyl promethazine sulfoxide and monodesmethyl promethazine. The lower limits of quantitation (LLOQ) were 3.75 ng/ml with less than 6.2% C.V. for PMZ and 2.50 ng/ml with less than 11.5% C.V. for metabolites based on a signal-to-noise ratio of 10:1 or greater. The accuracy and precision were within +/- 11.8% in bias and not greater than 5.5% C.V. in intra- and inter-assay precision for PMZ and metabolites. Method robustness was investigated using a Plackett-Burman experimental design. The applicability of the analytical method for pharmacokinetic studies in humans is illustrated.

A new goldfish model to evaluate pharmacokinetic and pharmacodynamic effects of drugs used for motion sickness in different gravity loads.

This paper proposes a new goldfish model to predict pharmacodynamic/pharmacokinetic effects of drugs used to treat motion sickness administered in differing gravity loads. The assumption of these experiments is that the vestibular system is dominant in producing motion sickness and that the visual system is secondary or of small import in the production of motion sickness. Studies will evaluate the parameter of gravity and the contribution of vision to the role of the neurovestibular system in the initiation of motion sickness with and without pharmacologic agents. Promethazine will be studied first. A comparison of data obtained in different groups of goldfish will be done (normal vs. acutely and chronically bilaterally blinded vs. sham operated). Some fish will be bilaterally blinded 10 months prior to initiation of the experiment (designated the chronically bilaterally blinded group of goldfish) to evaluate the neuroplasticity of the nervous system and the associated return of neurovestibular function. Data will be obtained under differing gravity loads with and without a pharmacological agent for motion sickness. Experiments will differentiate pharmacological effects on vision vs. neurovestibular input to motion sickness. Comparison of data obtained in the normal fish and in acutely and chronically bilaterally blinded fish with those obtained in fish with intact and denervated otoliths will differentiate if the visual or neurovestibular system is dominant in response to altered gravity and/or drugs. Experiments will contribute to validation of the goldfish as a model for humans since plasticity of the central nervous system allows astronauts to adapt to the altered visual stimulus conditions of 0-g. Space motion sickness may occur until such an adaptation is achieved.

An unusual multiple drug intoxication case involving citalopram.

A 47-year-old male with a history of drug abuse and suicide attempts was found dead at home. The death scene investigation showed evidence of cocaine abuse and multiple drug ingestion. Citralopram, a new selective serotonin reuptake inhibitor, cocaine, oxycodone, promethazine, propoxyphene, and norpropoxyphene were identified and quantitated in the postmortem samples by gas chromatography-mass spectrometry. The concentration of citalopram in the femoral blood was 0.88 mg/L. The heart blood concentration was 1.16 mg/L. Femoral blood concentrations of the other drugs were as follows: cocaine, 0.03 mg/L; oxycodone, 0.06 mg/L; promethazine, 0.02 mg/L; propoxyphene, 0.02 mg/L; and norpropoxyphene, 0.07 mg/L. Other tissue samples were also analyzed. The concentrations of cocaine, oxycodone, promethazine, and propoxyphene in the blood, liver, brain, and gastric contents did not suggest an intentional overdose. However, the possibility of multiple drug interactions including citalopram was evident. In this case, the citalopram concentrations were consistent with those reported in fatal cases involving multiple drug use. Citalopram was present in urine at a concentration of 0.9 mg/L.

Promethazine as a motion sickness treatment: impact on human performance and mood states.

PURPOSE: Intramuscular (i.m.) injections of promethazine in 25 mg or 50 mg dosages are commonly used to treat space motion sickness in astronauts. The present study examined the effects of i.m. injections of promethazine on performance, mood states, and motion sickness in humans. METHODS: Subjects were 12 men, mean age 36 + 3.1, who participated in 1 training day and 3 treatment conditions: a 25-mg injection of promethazine, a 50-mg injection of promethazine, and a placebo injection of sterile saline. Each condition, scheduled at 7-d intervals, required an 8-10-h day in which subjects were tested on 12 performance tasks, and were given a rotating chair motion sickness test. On the training day subjects were trained on each task to establish stability and proficiency. Treatment conditions were counterbalanced and a double-blind procedure was used to administer the medication or placebo. RESULTS: Statistically significant decrements in performance were observed for both dosages of promethazine as compared with the placebo. Performance decrements were associated with mean blood alcohol dose equivalency levels of 0.085% for 25 mg and 0.137% for 50 mg doses. Mood scale results showed significant changes in individual subjective experiences with maximum deterioration in the arousal state and fatigue level. Only the 25-mg dosage significantly increased motion sickness tolerance when compared with the placebo. CONCLUSIONS: These data suggest that effective doses of promethazine currently used to counteract motion sickness in astronauts may significantly impair task components of their operational performance.

Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects.

The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied. The study had an open-label, randomized, crossover design. At intervals of five to nine days, healthy volunteers were given two 12.5-mg promethazine rectal suppositories, one 25-mg suppository, one 50-mg suppository, or 50 mg (10 mL) of promethazine oral syrup. Blood samples were collected before each dose and at intervals from 0.5 to 48 hours afterward. Promethazine concentration was determined by high-performance liquid chromatography, and pharmacokinetic values were calculated with noncompartmental methods. Thirty-six subjects (18 men and 18 women) completed the study. Absorption was highly variable for all the formulations. On average, absorption was more rapid and the maximum plasma concentration (Cmax) higher for the syrup than for the suppositories. Cmax was significantly lower for the 50-mg suppository (mean, 9.04 ng/mL) than for the syrup (19.3 ng/mL). The time to Cmax (tmax) was significantly shorter for the syrup (mean, 4.4 hours) than for the suppositories (6.7-8.6 hours). There were no significant differences in dose-normalized Cmax among the three suppository treatments. Area under the concentration-versus-time curve (AUC) was comparable between the syrup and the 50-mg suppository and between the treatments with two 12.5-mg suppositories and the 25-mg suppository. Elimination profiles were similar among all treatments (mean half-life [t1/2], 16-19 hours). There were no significant differences in pharmacokinetics on the basis of sex or race. The mean relative bioavailability for the three suppository treatments ranged from 70% to 97%. Individual relative bioavailabilities ranged from 4% to 343%. The pharmacokinetics of promethazine administered in oral syrup and rectal suppositories were highly variable, but, in general, the suppositories produced a lower Cmax and later tmax than the syrup. All formulations were comparable in terms of dose-normalized AUC and t1/2, and the three suppository treatments were comparable in terms of dose-normalized Cmax.

Prokinetic effects of erythromycin after antimotion sickness drugs.

Motion sickness and the antimotion sickness drugs scopolamine (SCP) and promethazine (PMZ) inhibit gastric emptying (GE). This study was conducted to determine if erythromycin would exert its well-known prokinetic effects in normal and motion-sick subjects given antimotion sickness drugs. Fifteen fasted volunteers (11 males, 4 females) participated in the study. In control tests, 8 subjects were given intramuscular (i.m.) saline (SAL, 0.5 ml), SCP (0.1 mg), or PMZ (25 mg). GE of liquid (300 ml) containing 1 mCi of Tc 99m diethylenetriaminepentaacetic acid (DTPA) was measured by sequential gastric scintigraphy 30 minutes after i.m. treatments. In other tests, GE was measured in 8 subjects after each i.m. treatment, followed 10 minutes later by 200 mg of erythromycin ethylsuccinate (ESS) suspension given orally. In a third group of tests, 7 subjects received an i.m. treatment, oral EES 10 minutes later, and were then brought to an advanced level of motion sickness short of vomiting. To induce motion sickness, blindfolded subjects made timed head movements while seated in a rotating chair. GE was measured immediately after rotation. GE half-life, rate constant, area under the curve (AUC), and lag time were calculated using conventional mathematical methods for analyzing exponential rate processes. GE parameters calculated for normal and motion-sick subjects given antimotion sickness drugs and EES were compared with those from subjects given i.m. treatments (control) only. In normal subjects, EES significantly (p < 0.05) increased the GE rate constant for all i.m. treatments and reduced the AUC for SAL, SCP, and PMZ by 49% (p < 0.05), 44% (p < 0.05), and 69% (p < 0.01), respectively. In motion-sick subjects, lag time was significantly (p < 0.05) increased, and the rate constant and AUC values were unchanged from control for all i.m. treatments. The authors conclude that oral EES reverses the gastrostatic actions of the antimotion sickness drugs but does not affect the inhibition of gastric emptying associated with motion sickness. The results suggest that motion sickness and antimotion sickness drugs reduce GE through different mechanisms.