title: Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats.
abstract: This study was performed to determine biopharmaceutical properties of lobeglitazone (LB), a novel thiazolidinedione-based activator of peroxisome proliferator-activated receptor gamma, in rats. In parallel artificial membrane permeability assay and Madin-Darby canine kidney (MDCK) cell permeability assays of LB, the activator was found to interact with multidrug-resistance protein 1 (MDR1) and OATP1B1. The concentration resulting in 50% inhibition value for LB in MDR1 expressing MDCK cells was approximately 12.5 ± 3.61 μM. LB had adequate stability (i.e., 56% remaining at 0.5 h) in rat liver microsomes. A cytochrome P450 (CYP) inhibitory potency study indicated that LB is primarily interacted with CYP1A2, 2C9, and 2C19. In rats, LB appeared to be readily absorbed after an oral administration (an absolute bioavailability of ∼95%). Following intravenous administration, LB exhibited linear pharmacokinetics in the dose range of 0.5-2 mg/kg. The primary distribution site was the liver but it was also distributed to heart, lungs, and fat tissue. The excretion of LB to the urine, bile, feces, and intestine was insignificant (i.e., <10% of the dose) in rats. These observations suggest that, despite the fact that it interacts with some drug transporters and metabolizing enzymes, the pharmacokinetics of LB were linear with a high oral bioavailability.
authors: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 151-742, South Korea.|Korea Institute of Toxicology, Yuseong-gu, Daejeon, 305-343, South Korea.
authors: Jong-Hwa
authors: JH
authors: Lee
authors: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 151-742, South Korea.
authors: Chi-Kyoung
authors: CK
authors: Noh
authors: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 151-742, South Korea.
authors: Chang-Soon
authors: CS
authors: Yim
authors: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 151-742, South Korea.
authors: Yoo-Seong
authors: YS
authors: Jeong
authors: Department of Drug Discovery Platform Technology, Korea Research Institute of Chemical Technology (KRICT), Yuseong-gu, Daejeon, South Korea.
authors: Sung Hoon
authors: SH
authors: Ahn
authors: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 151-742, South Korea.
authors: Wooin
authors: W
authors: Lee
authors: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 151-742, South Korea.
authors: Dae-Duk
authors: DD
authors: Kim
authors: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 151-742, South Korea.
authors: Suk-Jae
authors: SJ
authors: Chung
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D007408:Intestinal Absorption / Q000502:physiology*; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000378:metabolism* / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000502:physiology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; D047495:PPAR gamma; D011743:Pyrimidines; D045162:Thiazolidinediones; D003577:Cytochrome P-450 Enzyme System; C089946:2,4-thiazolidinedione; C546215:lobeglitazone
keywords: ADME; CYP enzymes; P-glycoprotein; microsomal stability; pharmacokinetics; transporters