title: Oral tacrolimus oil formulations for enhanced lymphatic delivery and efficient inhibition of T-cell's interleukin-2 production.
abstract: Oral oil formulations have been reported to deliver drugs into the lymph. Lymphatic delivery of immunomodulatory drugs can more efficiently expose the drugs to T-cells in lymph, consequently induce higher efficacy and lower side effects. In this study, effects of tacrolimus oral oil formulations on drug blood exposure, and on inhibition of T-cell's interleukin-2 (IL-2) production were investigated in rats. Oil formulations (sunflower oil, cacao butter, medium chain triglyceride, and palm oil) dissolving tacrolimus showed lower drug blood concentration than a solid dispersion formulation (SDF). The sunflower oil, and cacao butter formulations suppressed drug blood exposure to 50% of the SDF, and inhibited T-cell's IL-2 production similar to the SDF. In vitro digestion tests indicated that slower digestion of the oils might reduce amount and rate of tacrolimus blood absorption. The cacao butter formulations showed 3.0 times more rapid tacrolimus absorption to lymphatic fluid than the SDF. Ratio of the rate constants of absorption into lymph to that into blood was higher in oil formulations (15 times in cacao butter, 15 times sunflower oil, and 3.5 times palm oil) than in the SDF. These results indicated that the oral oil formulations might be suitable for reduced tacrolimus blood concentration for low systemic side effects, and keep high lymph concentration for high efficacy in organ transplantation patients.
authors.affiliation: Drug Delivery, Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan. Electronic address: takayuki.yoshida@astellas.com.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Drug Delivery, Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Kiyo
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: Drug Delivery, Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Tatsunobu
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Drug Delivery, Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Tsutsui
authors.affiliation: Drug Delivery, Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Drug Delivery, Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Drug Delivery, Pharmaceutical Research and Technology Labs., Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sako
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D004041:Dietary Fats / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008198:Lymph Nodes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D000073878:Palm Oil; D010938:Plant Oils / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D000074242:Sunflower Oil; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D004041:Dietary Fats; D007376:Interleukin-2; D010938:Plant Oils; D000074242:Sunflower Oil; C052387:cocoa butter; D000073878:Palm Oil; D016559:Tacrolimus
keywords: Absorption rate; Interleukin-2; Intestinal lymphatic delivery; Oral oil formulation; Tacrolimus