title: Nanostructured lipid carriers as a novel oral delivery system for triptolide: induced changes in pharmacokinetics profile associated with reduced toxicity in male rats.
abstract: After oral administration in rodents, triptolide (TP), a diterpenoid triepoxide compound, active as anti-inflammatory, immunosuppressive, anti-fertility, anti-cystogenesis, and anticancer agent, is rapidly absorbed into the blood circulation (from 5.0 to 19.5 minutes after dosing, depending on the rodent species) followed by a short elimination half-life (from about 20 minutes to less than 1 hour). Such significant and rapid fluctuations of TP in plasma likely contribute to its toxicity, which is characterized by injury to hepatic, renal, digestive, reproductive, and hematological systems. With the aim of prolonging drug release and improving its safety, TP-loaded nanostructured lipid carriers (TP-NLCs), composed of Compritol® 888 ATO (solid lipid) and Capryol™ 90 (liquid lipid), were developed using a microemulsion technique. The formulated TP-NLCs were also characterized and in vitro release was evaluated using the dialysis bag diffusion technique. In addition, the pharmacokinetics and toxicology profiles of TP-NLCs were compared to free TP and TP-loaded solid lipid nanoparticles (TP-SLNs; containing Compritol 888 ATO only). Results demonstrate that TP-NLCs had mean particle size of 231.8 nm, increased drug encapsulation with a 71.6% efficiency, and stable drug incorporation for over 1-month. TP-NLCs manifested a better in vitro sustained-release pattern compared to TP-SLNs. Furthermore, TP-NLCs prolonged mean residence time (MRT)0-t (P<0.001, P<0.001), delayed Tmax (P<0.01, P<0.05) and decreased Cmax (P<0.01, P<0.05) compared to free TP and TP-SLNs, respectively, which was associated with reduced subacute toxicity in male rats. In conclusion, our data suggest that TP-NLCs are superior to TP-SLNs and could be a promising oral delivery system for a safer use of TP.
authors.affiliation: National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan.
authors.forename: Fan
authors.initials: F
authors.lastname: Peng
authors.affiliation: National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan.
authors.forename: Jiangling
authors.initials: J
authors.lastname: Wan
authors.affiliation: National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan.
authors.forename: Chunxi
authors.initials: C
authors.lastname: Wan
authors.affiliation: National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan ; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, People's Republic of China.
authors.forename: Huibi
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, People's Republic of China.
authors.forename: Christopher Waikei
authors.initials: CW
authors.lastname: Lam
authors.affiliation: National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan ; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, People's Republic of China.
authors.forename: Xiangliang
authors.initials: X
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D004224:Diterpenes / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004655:Emulsions; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D050997:Nanomedicine; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D004337:Drug Carriers; D004655:Emulsions; D004852:Epoxy Compounds; D008055:Lipids; D010616:Phenanthrenes; C001899:triptolide
keywords: in vivo pharmacokinetics; microemulsion technique; rat subacute toxicity; sustained-release; triptolide