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


Am J Health Syst Pharm. 2000;57(16) 

In This Article

Abstract and Introduction

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 tmaxthan 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.

Promethazine hydrochloride is a phenothiazine derivative that is structurally different from the antipsychotic phenothiazines. Promethazine is a histamine H1 -receptor antagonist with moderate muscarinic dopamine (D2)-receptor-blocking effects. Since its introduction in 1946, promethazine has been used in a variety of clinical situations: for the prevention and treatment of nausea and vomiting caused by narcotiCtherapy,[1] migraines,[2] and cancer chemotherapy [3]; as a sedative, particularly as part of a preoperative drug regimen and during labor [4,5,6]; and for motion sickness.[7]

Promethazine hydrochloride is well absorbed from the gastrointestinal tract, although a significant portion of a dose is subject to first-pass metabolism. Clinical effects are apparent within 20 minutes after oral, rectal, or intramuscular administration, and the effects last four to six hours.[8] Promethazine undergoes extensive hepatic metabolism to a variety of metabolites. The sulfoxides of promethazine and N-demethylpro-methazine are the predominant metabolites and are excreted in the urine. Negligible amounts of unchanged drug are recovered in the urine.[9]

Several studies have evaluated the pharmacokinetics of promethazine hydrochloride administered by different routes. In a study comparing a 50-mg suppository with oral syrup (50 mg), absorption of both promethazine formulations exhibited pronounced variability, with coefficients of variation greater than 84% for the area under the plasma concentration- versus-time curve (AUC).[9] The mean AUC from 0 to 24 hours (AUC0-24 ) for the suppository was 168 ng x hr/mL, compared with 268 ng x hr/mL for the oral syrup. Another study compared a generic promethazine hydrochloride 50-mg suppository with a brand-name preparation of promethazine hydrochloride oral syrup (50 mg) and with a brand-name 50-mg suppository.[10] Both suppository treatments yielded a lower maximum promethazine concentration and a longer time to maximum promethazine concentration than did the oral syrup. However, there were no significant differences in AUC0-24. Both suppository treatments and the oral syrup demonstrated high variability with respect to promethazine pharmacokinetics. The pharmacokinetics of intravenous and oral promethazine have also been compared.[11] On average, 88% of a promethazine dose is absorbed after oral administration; however, the absolute bioavailability is only 25% because of first-pass clearance.

This study compared the pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup to healthy subjects. The study was performed to comply with a regulatory request from the Food and Drug Administration. The specific purpose was to examine the dose proportionality of the three suppository dosage strengths and to assess the bioavailability of promethazine for the three suppository strengths relative to the syrup.


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