Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein binding

Abstract

It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After intravenous administration of omeprazole to NARs, the Cl(nr) was significantly faster than in the controls (110 versus 46.6 ml/min/kg), and this could be due to an increase in hepatic metabolism caused by a greater hepatic CYP1A2 level in addition to greater free fractions of the drug in NARs. After oral administration of omeprazole to NARs, the AUC was also significantly smaller (80.1% decrease) and F was decreased in NARs. This could be primarily due to increased hepatic and intestinal metabolism caused by greater hepatic CYP1A2 and intestinal CYP1A and 3A levels. In particular, the smaller F could mainly result from greater hepatic and intestinal first-pass effect in NARs than in the controls.

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

“…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.…”

“…[28] After i.v. administration of omeprazole to male NARs, its plasma CLNR (which could represent its CLH [60,61] ) was more rapid (by 136%) than that in control rats [8] ( Table 3). This could be due to the faster hepatic CLint for the disappearance of omeprazole (by 37.0% and 75.6%, based on ml/min per mg protein and ml/min per g liver, respectively) because of an increased protein expression of hepatic CYP1A2 (Table 1), and greater (by 112%) fp than those in control rats (Table 3) because QH did not seem to be altered in the NARs.…”

“…The protein-binding values of omeprazole to 4% HSA remain constant (91.7%) at omeprazole concentrations ranging from 1 to 200 μg/ml. [8] The plasma protein-binding value of omeprazole in NARs (60.7%) could be due to binding to 1.8% βplus 0.63% γ-globulins (46.0%), 0.63% γ-globulin (36.0%) and 1.3% γ-globulin (40.5%) because the value for 0.0042% HSA was only 8.14%. [8] Oltipraz (an intermediate-hepatic extraction ratio drug, direct hepatic extraction ratio 0.4 [62] )…”

“…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]…”

Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and β-naphthoflavone

“…However, the concentration of OPZ was 6,053 ± 2,409 ng/ml in the High OPZ group and 310 ± 241 ng/ml in the OPZ+BNF group. OPZ is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats (Lee et al, 2009). In the OPZ+BNF group, the expression of Cyp1a1 and 1a2 increased when compared with the Low OPZ and Low BNF groups.…”