Research Articles
Tacrolimus is a class II low-solubility high-permeability drug: The effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats

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Abstract

The objective of this study is to investigate the role of P-glycoprotein (P-gp), a membrane efflux pump associated with multidrug resistance (MDR) and a known substrate for tacrolimus, in determining the regional intestinal permeability of tacrolimus in rats. Thus, isolated segments of rat jejunum, ileum, or colon were perfused with tacrolimus solutions containing polyethoxylated hydrogenated castor oil 60 surfactant, and with or without verapamil, a P-gp substrate used to reverse the MDR phenotype. The results indicated that the intrinsic permeability of tacrolimus in the jejunum, calculated on the basis of the concentration of non-micellized free tacrolimus, was quite high (∼ 1.4 × 10−4 cm/s). The apparent permeability (Papp) in the jejunum was unaffected by the presence of verapamil; however, the Papp in the ileum and the colon increased significantly in the presence of verapamil and were similar to the values observed in the jejunum. The results suggest that systemic absorption of tacrolimus from the gastrointestinal tract could be significantly affected by P-gp efflux mechanisms. It is also possible that differences in P-gp function at various intestinal sites in a subject or at a given intestinal site in various subjects could lead to large intra- and interindividual variability in bioavailability of tacrolimus following oral administration. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:719–729, 2002

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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