Pharmacokinetics of Promethazine Hydrochloride After Administration of Rectal Suppositories and Oral Syrup to Healthy Subjects

Laura C. Strenkoski-Nix, James Ermer, Sheryl Decleene, William Cevallos, and Philip R. Mayer

Disclosures

Am J Health Syst Pharm. 2000;57(16) 

In This Article

Methods

The study was performed at Corning Besselaar clinical research units and was approved by Corning Besselaar's institutional review board. Volunteers' informed consent was obtained before they participated. Volunteers were screened for eligibility for the study within two weeks before study day 1. Healthy adults of either sex with an age between 18 and 45 years and a body weight within 15% of the ideal weight for their sex, height, and body frame were eligible for participation. A medical history (including, for women, a menstrual history) was obtained; a physical examination (including an anoscopic examination) was performed; and vital signs, a 12- lead electrocardiogram (ECG), and a clinical laboratory profile (serum chemistry, hematology, and urinalysis) were obtained. The volunteers were healthy, with no significant abnormalities in the laboratory test results. They reported that they were free of alcohol and illicit drug abuse (for at least the past 12 months), tobacco use (3 months), prescription drug and investigational drug use (1 month), and nonprescription drug use (7 days). The use of a nonhormonal birth-control method was required for female study participants, and a negative serum pregnancy test was required before administration of study medication. Women who were breast-feeding were excluded from the study.

The study had an open-label, four-period, crossover design. The subjects received the following four treatments in a randomized sequence at intervals of five to nine days: two 12.5-mg Phenergan rectal suppositories (treatment A),[a] one 25- mg Phenergan rectal suppository (treatment B),[b] one 50-mg Phenergan rectal suppository (treatment C),[c] and 50 mg (10 mL) of Phenergan Syrup Fortis, given orally (treatment D).[d] Volunteers were admitted to the study center 12 hours (at approximately 8 p.m.) before each dose was administered. A clinical laboratory evaluation was performed and an overnight fast was begun. Water was allowed until one hour before drug administration. An enema [e] was administered two hours before suppository insertion. Vital signs (temperature, blood pressure, and pulse) were measured before a dose and 24 and 48 hours afterward. The volunteers received the test medication at approximately 8 a.m. Venous blood samples (7 mL each) for promethazine concentration assay were drawn before a dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours afterward. Unrestricted access to water was allowed, except within one hour of a dose. Bed rest was recommended for the first hour after suppositories were inserted.

No strenuous activity was permitted during the confinement periods. The subjects were provided with the same medium-fat diet (fat contributing 28-32% of total calories) during each confinement period and were limited to three meals per day and one afternoon or evening snack. Grapefruit juice, alcohol, and caffeine- containing products were not permitted. The subjects were discharged from the study unit after the final blood sampling at hour 48.

A complete clinical evaluation was performed after the last blood sample was obtained for study period 4 (before discharge). This included a complete physical examination, a clinical laboratory profile, vital signs, a 12-lead ECG, and, for women, a pregnancy test (serum beta-human chorionic gonadotropin).

The blood samples were collected in 7-mL Vacutainer tubes [f] containing heparin; the tubes were inverted gently four or five times and then centrifuged (2500-3000g) at 4 °C. Processing occurred as quickly as possible after blood collection. The plasma was transferred to polypropylene screw-cap tubes, transferred to a freezer (-20 °C or colder), and stored upright until assayed. The promethazine assay consisted of a validated high-performance liquid chromatographic method 12 with electrochemical detection.g After an internal standard was added, promethazine was extracted by liquid- liquid extraction, and separation was accomplished with a heated Zorbax Rx-C8 analytical column.h Concentrations of promethazine were quantitated by using an electrochemical detector with a working electrode (850 mV) against a silver-silver chloride reference electrode. On the basis of peak height ratios, the range of the assay was 0.05 to 10 ng/mL. Three quality-control (QC) concentrations were used: 0.150, 1.50, and 7.50 ng/ mL. A minimum of six QC samples were included in each assay run, and at least two thirds of the QC samples were within 15% (intermediate and high QC) or 20% (low QC) of the nominal concentrations. If the promethazine concentration was >10 ng/mL, the sample was diluted (generally 1:4) and reassayed. When dilutions were performed, 7.5- and 20- ng/mL QC samples were included. The relative standard deviation (RSD) for the QC samples was 7.0% for 7.5 ng/mL, 7.2% for 1.5 ng/mL, and 12.0% for 0.150 ng/mL. The RSD for the diluted QC samples was 5.0% at 20.0 ng/mL and 5.2% at 7.50 ng/mL.

Pharmacokinetic values were calculated by using PC Nonlin, version 4.2 (Statistical Consultants Inc., Lexington, KY). Noncompartmental methods were used. The maximum plasma promethazine concentration (Cmax ) and the time to Cmax (tmax) were determined from observed data. The terminal-phase disposition rate constant ( z) was estimated by linear regression of the natural log-transformed terminal-phase promethazine concentrations. The half-life (t1/2) was calculated by the equation t1/2 = 0.693/ z. The AUC from time zero to the time of the last measured concentration (AUC0-t ) was determined with the linear trapezoidal rule. The AUC from time zero to infinity (AUC0- ) was calculated by the equation AUC0- = AUC0-t + (Ct / z), where Ct is the last measured concentration. Clearance (CL/F) was determined from the relationship CL/F = dose/AUC0- , and apparent volume of distribution (V/F) was calculated from CL/F/ z. CL/F and V were normalized by body weight. Percent relative bioavailability was determined from the relationship {[AUC0- (suppository) x dose (oral)]/[AUC0- (oral) x dose (suppository)]} x 100.

Summary statistics were calculated for all subjects and for subgroups identified by race and sex. Statistical comparisons were performed by using the SAS for Windows, release 6.12, general linear model (GLM) procedure (SAS Institute Inc., Cary, NC). A parametric (normal theory) GLM was applied to the variables Cmax, tmax, t1/2, AUC0-t, and AUC0- and the dose-normalized variables Cmax, AUC0-t, and AUC0- . The analysis of variance included the following factors: (1) subject within sequence by sex and race, (2) sex, (3) race, (4) treatment by sex interaction, (5) treatment by race interaction, (6) sequence, (7) period, and (8) treatment. Sequence, sex, and race effects were tested using subject within sequence by sex and race as the error term, and all other effects were tested using the overall mean square error. If there was a significant difference between treatments, pairwise comparisons were made with a Bonferroni t test. The a priori level of significance was 0.05.

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