Ipriflavone pharmacokinetics in mutant Nagase analbuminemic rats

Abstract

Ipriflavone, a derivative of naturally occurring isoflavones, was primarily metabolized in rats via hepatic CYP1A1/2 and 2C11. Protein and mRNA expression of CYP1A2 in the liver, reported to be increased in mutant Nagase analbuminemic rats (NARs), should influence the pharmacokinetic parameters of ipriflavone. In this study, the contribution of hepatic CYP2C11 and intestinal CYP1A protein to the metabolism and the pharmacokinetic parameters of ipriflavone were examined after intravenous (20 mg/kg) and oral (200 mg/kg) administration to male Sprague-Dawley (control) rats and NARs. There was no change in the protein expression of hepatic CYP2C11. By contrast, CYP1A protein of the intestine increased by almost 100%. After the intravenous administration of ipriflavone to NARs, the Cl(nr) and AUC were unchanged, suggesting that the contribution of the increase in protein expression and mRNA level of hepatic CYP1A2 to hepatic metabolism of the drug in NARs seemed to be almost negligible. However, after the oral administration of ipriflavone to NARs, the AUC was significantly lower than that in the control rats (53.0% decrease), possibly due to the increased intestinal CYP1A that resulted in increased intestinal metabolism and decreased gastrointestinal absorption of ipriflavone in NARs.

Pharmacokinetics of drugs in mutant Nagase analbuminemic rats and responses to select diuretics

“…[45] After i.v. administration of ipriflavone to male NARs, its plasma CLNR was comparable with control rats [7] (Table 3). This could be supported by the comparable hepatic CLint for the disappearance of ipriflavone and the comparable fp for both types of rats.…”

“…where GI24 h represents the fraction of the dose remaining in the GI tract at 24 h (including its contents and faeces). The fractions of the oral dose absorbed (fabs; 1 − funabs) of omeprazole (0.982 and 0.990 for control rats and NARs, respectively [8] ), oltipraz (0.933 and 0.890, respectively [29] ) and ipriflavone (0.843 and 0.763, respectively [7] ) were found to be similar between the control rats and NARs. The GI absorption of gliclazide was also reported to be comparable between the two types of rats.…”

“…This could be supported by the comparable hepatic CLint for the disappearance of ipriflavone and the comparable fp for both types of rats. [7] Based on the CLR,fp (Table 3), ipriflavone is excreted in the urine via active renal tubular re-absorption for both types of rats. The protein-binding values of ipriflavone to 4% HSA remain constant (96.6%) at ipriflavone concentrations ranging from 1 to 200 μg/ml.…”

“…The reason for changes in CLNR was also explained. (2) Pharmacokinetic changes of drugs in NARs ↑ 250% [6] CYP1A subfamily ↑ 100% [7] CYP2B1/2 ↓ 75.5% [6] CYP3A subfamily ↑ 110% [8]…”

“…Significantly greater 1-h biliary excretion (by 21.5%) [44] Drugs not altered pharmacokinetically in NARs 1 Ipriflavone (20 mg/kg [7] ) CYP1A1/2 and 2C11 [45] Comparable CLNR [7] 2…”