Pharmacokinetics and Dose Proportionality of Domperidone in Healthy Volunteers

Abstract

Domperidone is a potent gastrokinetic agent and antinauseant currently undergoing clinical trials in the United States. The bioequivalence of 20 mg of domperidone given as free-base tablets and maleate salt tablets, and the bioavailability of base and maleate tablets relative to a solution, were studied in 21 fasting men using a crossover design. Plasma samples collected for up to 48 hours were analyzed for domperidone levels, using a sensitive and specific radioimmunoassay (RIA). The absorption of domperidone was very rapid, with mean peak plasma concentration (Cmax) values of 18.8, 15.0, and 20.7 ng/mL attained at 0.9, 1.2, and 0.6 hours after the administration of base tablet, maleate tablet, and solution, respectively. The mean elimination half-life (t1/2) ranged from 12.6 to 16.0 hours. The mean oral clearance (CL/F) after the solution dose was 4,735 +/- 2,017 mL/min and the mean apparent volume of distribution (Vd/F) was 6,272 +/- 5,100 L, indicating an extensive distribution of domperidone in the body. The area under the plasma concentration-time curve (AUC) data demonstrated bioequivalence of base and maleate tablets. The relative bioavailability for base tablet and maleate tablet was 107 +/- 50% and 116 +/- 47%, respectively, of that of the solution. Dose proportionality of domperidone was also studied in 12 subjects at solution doses of 10, 20, and 40 mg. Linear correlations between the dose and Cmax and AUC values were observed. Mean CL/F remained relatively constant after doses of 10, 20, and 40 mg (5,255 +/- 3,159, 4,842 +/- 1,774, and 4,380 +/- 1,289 mL/min, respectively), indicating linear pharmacokinetics of domperidone over the dose range studied.

Quantitative determination of domperidone in human plasma by ultraperformance liquid chromatography with electrospray ionization tandem mass spectrometry

“…Figure 6 shows mean plasma concentration-time curves of domperidone after administration. The halflife varied from 0.33 to 1 h, similar to the results reported (Brogden et al, 1982;Huang et al, 1986;Kobylinska and Kobylinska, 2000).…”

“…Several methods have been investigated for the determination of domperidone in human plasma. Huang et al (1986) measured domperidone levels by a radioimmunoassay (RIA) method using antibodies raised against domperidone. However, antibodies raised in rabbits against domperidone are not commercially available.…”

Formulation and development of orodispersible sustained release tablet of domperidone

“…The drug plasma concentration declined rapidly thereafter with no drug being detected beyond 8 h. Domperidone undergoes rapid first pass metabolism though renal clearance is low 59 . Conventional formulation showed much shorter t1/2 as compared to that reported for humans.…”

Dose-dependent separation of dopaminergic and adrenergic effects of epinine in healthy volunteers

“…At present we can not explain why domperidone did not inhibit the decrease in prolactin induced but the 2.0 and 4.0 gg/kg/min doses of dopamine or epinine. It could be that the dose of domperidone was too low or, more likely, that due to its rapid metabolisation (Brogden et al 1982;Huang et al 1986) plasma levels might have decreased during the course of infusion (60 min) to values that were not sufficient to counteract the prolactin-decreasing effects of the higher doses of dopamine or epinine. Nevertheless, the fact that c~-and Mean-values _+ SEM of 5 experiments each are given as symbols with error bar.…”