首页|Gender differences and dose proportionality in the toxicokinetics of udenafil and its active metabolite following oral administration in rodents

Gender differences and dose proportionality in the toxicokinetics of udenafil and its active metabolite following oral administration in rodents

扫码查看
原文链接
  • NSTL
  • Elsevier
Udenafil is a long-acting oral phosphodiesterase type 5 inhibitor used to treat erectile dysfunction which may also have beneficial effects on cardiovascular diseases. Udenafil is mainly biotransformed to the active metabolite N-dealkylated udenafil via cytochrome P450 3A. The aim of this study was to investigate the gender differences and dose proportionality of the toxicokinetics of udenafil and its metabolite N-dealkylated udenafil in rodents. Udenafil was administered orally by gavage to male and female B6C3F1/N mice (100, 240, 350, and 500 mg/kg) and F344 rats (60, 120, and 240 mg/kg). Plasma concentrations of udenafil and N-dealkylated udenafil were simultaneous measured via liquid chromatography-tandem mass spectrometry. Female mice showed higher systemic exposure to udenafil than male mice, whereas female rats showed lower systemic exposure to udenafil than male rats after repeated administration at high dose. Systemic exposure to the metabolite, N-dealkylated udenafil, was lower in female than male mice and rats. A dose proportionality assessment by power model revealed a lack of dose proportionality in systemic exposure (C-max, AUC(2)(4h) and AUC(in)(f)) after administration of 100-500 mg/kg of udenafil in mice and 60-240 mg/kg in rats. This study thus demonstrates gender and species differences with regard to the toxicokinetic profiles of udenafil and its active metabolite N-dealkylated udenafil after oral administration of udenafil to mice and rats of both sexes. Our findings suggest the possibility of gender differences in the toxicokinetics of udenafil in humans and suggests that further study is needed in this cohort.

UdenafilToxicokineticsGender differencesDose proportionalityRodent

Lee, Jong-Hwa、Lee, Dae Young、Kang, Kyung Koo、Jeong, Eun Ju、Staatz, Christine E.、Baek, In-hwan

展开 >

Korea Inst Toxicol, Bioanaly & Pharmacokinet Study Grp, 141 Gajeong Ro, Daejeon 34114, South Korea

Dong A Socio R&D Ctr, 21 Geumhwa Ro,105beon Gil, Yongin 17073, Gyeonggi Do, South Korea

Korea Inst Toxicol, Chem Risk Assessment Res Comm, Daejeon, South Korea

Univ Queensland, Pharm Australia Ctr Excellence, Sch Pharm, 20 Cornwall St, Brisbane, Qld 4102

Kyungsung Univ, Coll Pharm, 309 Suyeong Ro, Busan 48434, South Korea

展开 >

2021

10.1016/j.taap.2020.115339

Toxicology and Applied Pharmacology

Toxicology and Applied Pharmacology

SCI
ISSN：0041-008X
年,卷(期)：2021.410
  • 28