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

Discussion

Promethazine hydrochloride is widely used for the treatment and prevention of mild to moderate nausea and vomiting. In these circumstances, the oral route is often not feasible. When i.v. or i.m. administration is not convenient, rectal administration is a reasonable alternative. As in other studies,[9,10,11] high variability in plasma promethazine concentrations was observed after oral administration. The variability in clearance after i.v. administration of promethazine to healthy volunteers was approximately 36%.[11] This is markedly lower than the 60.3% (oral) and 129-158% (rectal) variability in CL/F observed in the present study of oral and rectal promethazine. Thus, much of the variability may be attributed to variability in the bioavailability of promethazine for the oral and rectal formulations. A possible explanation is differences in first-pass metabolism among individual subjects. Some of the variability after rectal administration may be related to the site of absorption within the rectum[13] or to an altered first-pass effect due to variations in the rate of absorption.

A relationship between plasma promethazine concentrations and antiemetic efficacy has not been examined. Whether individuals with low serum concentrations are more likely not to respond to therapy remains to be determined. However, the limited effectiveness of phenothiazines for moderate to severe nausea has led to replacement with butyrophenones (e.g., haloperidol and droperidol), serotonin antagonists (e.g., ondansetron), and various combinations of antiemetics. Low serum concentrations in some patients may contribute to lack of efficacy. Intraindividual variability was not addressed in this study and may be a substantial component of the variability observed.

Absorption of promethazine from the rectal suppositories resulted in a mean 16% lower bioavailability compared with the 50-mg oral syrup. The syrup also resulted in an earlier and higher Cmax and lower variability than the suppositories. Although these results suggest that the syrup (or a bioequivalent tablet) should be used when possible, emesis and potential loss of a portion of the dose after oral administration must be considered in clinical settings. Rectal administration remains an option for treating nausea and vomiting.

In this study, Hispanics had higher mean Cmax and AUC values than white or black subjects. This could be the result of a difference in first-pass metabolism in Hispanics. However, the power of the study to detect differences by race was low, given the high variability observed.

The plasma promethazine t1/2 ranged from 9.5 to 30 hours for the syrup and from 4.3 to 34 hours for the suppositories. The mean t1/2 values (16-19 hours) were higher than those reported in the literature (10- 15 hours),9,10,12 probably because of the lower limit of detection of the promethazine assay (0.05 ng/mL) and the longer sampling period (48 hours) in this study than in the earlier studies. In a study of i.v. and oral promethazine,[11] the limit of detection of the assay was 0.2 ng/mL, and sampling was terminated at 27 hours.

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