Research ArticlesTacrolimus is a class II low-solubility high-permeability drug: The effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats
Section snippets
INTRODUCTION
Tacrolimus is a 23-member macrolide lactone (molecular weight = 803.5 Da) with potent immunosuppressive activity that has been shown to be effective in the prophylaxis of organ rejection following liver, heart, kidney, and small bowel transplantation.1., 2., 3., 4. It is commercially available as capsules for oral administration and as an injectable for intravenous infusion. Because of its poor solubility in water (4–12 μg/mL), intravenous dosage forms of tacrolimus contain surfactants and the
Materials
Tacrolimus was kindly provided by Fujisawa Pharmaceutical Company (Osaka, Japan). Polyoxyethylated hydrogenated castor oil 60 (HCO-60) was supplied by NIKKO Chemicals Company (Tokyo, Japan). Citric acid, dibasic sodium phosphate, and Econo 1, a liquid scintillation cocktail, were obtained from Fisher Scientific (Fair Lawn, NJ). Carbon-14-labeled polyethylene glycol 4000 ([14C]PEG4000) was purchased from Amersham Life Science (Arlington Heights, IL) and Spectra/Por® cellulose membranes were
Effect of HCO-60 on Permeability of Tacrolimus in Rat Jejunum
Because of the low solubility of tacrolimus in water and its nonspecific adsorption to glassware and perfusion equipment, it was not possible to obtain reproducible permeability results in the absence of stabilizing additives in the perfusion solution (data not shown). Thus, it was necessary to incorporate a nonionic surfactant, polyethoxylated hydrogenated castor oil (HCO-60), to the perfusion medium to solubilize tacrolimus and to prevent adsorption losses. The effect of HCO-60 inclusion at
DISCUSSION
In this report we describe perfusion studies in rats with tacrolimus solutions formulated in the presence of a nonionic surfactant, HCO-60. The results suggest that the intrinsic jejunal permeability of tacrolimus, obtained following correction of apparent permeability for free unmicellized tacrolimus is quite high. It is also evident that the intrinsic jejunal permeability of tacrolimus in rats is unaffected by the presence of the surfactant, indicating that inclusion of HCO-60 in the
CONCLUSIONS
The combined results of single-pass perfusion studies with rats indicate that tacrolimus is an intrinsically high-permeability drug. These studies also showed significant site-dependency of tacrolimus permeability in rat intestine. Thus, the permeability was highest from the jejunum, followed by ileum and colon. Perfusion studies in the presence of verapamil, a potent inhibitor of P-gp, showed that jejunal permeability was unaffected; however, ileal and colonic permeabilities were enhanced two-
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