Influence of the Hydrophilicity of Suppository Bases on Rectal Absorption of Carprofen, a Lipophilic Nonsteroidal Anti-Inflammatory Drug

Abstract

The influence of the hydrophilicity of fatty suppository bases on the rectal absorption of the lipophilic drug carprofen (octanol–buffer, pH 7.4; partition coefficient, 40) was investigated in dogs. Five animals received each of six carprofen formulations in a random sequence: intravenous, oral, and rectal solutions, and three suppository formulations. The suppository vehicles tested were semisynthetic glycerides containing saturated fatty acids mainly in the range of C10 to C18 [Massa Estarinum A (MEA), Massa Estarinum B (MEB), and Massa Estarinum 299 (ME299)]; their hydroxyl values increased from 1 for ME299, through 24 for MEB, to 45 for MEA. Following every drug administration, blood samples were collected over a period of 104 h and carprofen plasma concentrations were measured by a specific HPLC method with UV detection. The rate and extent of carprofen absorption were characterized by evaluation of the maximum plasma concentrations (Cmax), the time of their occurrence (tmax), absolute bioavailabilities, statistical moments, and by deconvolution. Carprofen was rapidly and completely absorbed from the oral solution. The maximum concentrations obtained with oral solutions were significantly higher than those observed with rectal solutions and with the three suppository formulations. Results obtained with the rectal solution exhibited a high degree of intersubject variability. After rectal administration of suppositories, the rate and extent of carprofen absorption increased with the hydroxyl value of the suppository base; the mean absorption times (MAT) and tmax were shorter with MEA (2.15 and 1.7 h, respectively) than with the less hydrophilic vehicles (MEB: 4.09 and 2.1 h, respectively; ME299: 4.22 and 2.4 h, respectively). The mean plasma concentrations of carprofen observed after rectal administration rose with increasing hydrophilicity of the suppository base. On the other hand, Cmax and partial areas under the curves from 0 to 8 h after administration of the lipophilic ME299 were lower (21.2 mg/L and 119.1 h · mg/L, respectively) than those obtained with the other, more hydrophilic suppository formulations (MEB: 27.0 mg/L and 152.1 h · mg/L, respectively; MEA: 30 mg/L and 171.8 h · mg/L, respectively). Fractions of the dose of carprofen absorbed from the suppository vehicle ME299 (0.53) during the 6 h following drug administration were lower than those absorbed from vehicles MEB (0.69) and MEA (0.72).