title: Naringenin interferes with the anti-diabetic actions of pioglitazone via pharmacodynamic interactions.
abstract: Pioglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) full agonist and useful for the treatment of type 2 diabetes mellitus. Naringenin is a citrus flavonoid with anti-inflammatory actions, which has been shown to prevent obesity-related diseases and to activate PPARγ. The aim of this study was to investigate whether dietary naringenin affects the actions of pioglitazone. We administered naringenin (100 mg/kg) and pioglitazone (10 mg/kg) to Tsumura Suzuki Obese Diabetes (TSOD) mice for 4 weeks and then conducted an oral glucose tolerance test. We found that oral administration of naringenin attenuated the hypoglycemic action of pioglitazone in TSOD mice. However, pioglitazone and naringenin did not affect fasting blood glucose levels, epididymal fat pad weight and body weight changes in this administration period. Pioglitazone suppressed expression of obesity-related adipokines such as tissue inhibitor of metalloproteinases-1 in adipose tissue of TSOD mice, but this effect was attenuated by naringenin. However, naringenin did not affect the pharmacokinetics of pioglitazone after single or repeated administration. Naringenin exhibited weak partial agonist activity in time-resolved fluorescence resonance energy transfer assay, but naringenin interfered with pioglitazone agonism, consistent with partial agonism. Our results suggest that it is advisable to avoid administering a combination of naringenin and pioglitazone.
authors.affiliation: Department of Biochemistry, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan. h-yoshida@phoenix.ac.jp.
authors.forename: Hiroki
authors.identifier: http://orcid.org/0000-0002-6903-2401
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Biochemistry, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Tsuhako
authors.affiliation: Department of Pharmacognosy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Atsumi
authors.affiliation: Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Narumi
authors.affiliation: Department of Microbiology, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Watanabe
authors.affiliation: Department of Biochemistry, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sugita
authors.affiliation: Department of Biochemistry, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004347:Drug Interactions; D044950:Flavanones / Q000008:administration & dosage / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D044950:Flavanones; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; C005273:naringenin; D000077205:Pioglitazone
keywords: Food−drug interaction; Naringenin; PPARγ; Pioglitazone