Aldehyde oxidase-dependent species difference in hepatic metabolism of fasudil to hydroxyfasudil.
1. An investigation on the metabolic mechanism of fasudil to hydroxyfasudil was conducted in vitro using liver subcellular fractions of different species. Hydroxyfasudil was generated in large amounts by rat liver S9 and to a similar extent by human liver S9 but was not detected in dog liver S9 incubations. 2. Studies with various molybdenum hydroxylase inhibitors demonstrated that aldehyde oxidase (AO), but not xanthine oxidase (XO), selectively catalyzed fasudil to hydroxyfasudil in both rat and human liver cytosol. In addition, the oxygen atom incorporated into hydroxyfasudil was derived from water rather than atmospheric oxygen, which further corroborated AO involvement. 3. Enzyme kinetics experiments revealed that fasudil had a higher affinity to human hepatic AO than to rat hepatic AO. Besides, significantly different in vivo pharmacokinetic parameters observed between male and female rats indicated that the AO activity in rats was gender-dependent. 4. The present study provided first evidences that AO causes differences in fasudil metabolism between species.
a Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University , Shenyang , China.
Zhengsheng
Z
Mao
a Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University , Shenyang , China.
Yali
Y
Wu
a Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University , Shenyang , China.
Qiuying
Q
Li
a Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University , Shenyang , China.
Xin
X
Wang
a Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University , Shenyang , China.
Youping
Y
Liu
a Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University , Shenyang , China.
Xin
X
Di
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000378:metabolism; D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D004285:Dogs; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D014969:Xanthine Oxidase
D047428:Protein Kinase Inhibitors; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D014969:Xanthine Oxidase; D042931:Aldehyde Oxidase; C049347:fasudil
Aldehyde oxidase; Rho-associated kinase inhibitor; fasudil; species difference; xanthine oxidase