Effects of Itraconazole, Dexamethasone and Naringin on the Pharmacokinetics of Nadolol in Rats

Summary:The aim of the present study was to clarify the involvement of P-glycoprotein (P-gp) or organic anion transporting polypeptide (Oatp) 1a5 in the pharmacokinetics of nadolol (NDL), a non-metabolized hydrophilic β-adrenoceptor blocker, in rats. Pretreatment with itraconazole (ICZ, P-gp inhibitor, 50mg/kg) for 30min before oral administration of NDL (10mg/kg) significantly increased the area under the plasma concentration-time curve (AUC∞) of NDL by 1.7-fold compared with control. Intragastric administration of dexamethasone (DEX, 8mg/kg) for 4 consecutive days increased P-gp level in the intestine and the liver. In line with this, DEX pre-treatment decreased maximum plasma concentration (Cmax) of NDL by 28% of control. To inhibit the intestinal Oatp1a5, naringin (NRG, 0.145 mg/kg) was preadministered orally for 30 min before the oral administrations of NDL or celiprolol (CEL, 10 mg/kg, Oatp1a5 substrate). Although NRG markedly reduced Cmax and AUC∞ of CEL by 60% and 65% of control, respectively, little difference was observed in the plasma concentration of NDL between NRG and control. These results suggest that P-gp is greatly involved in the pharmacokinetics of NDL, while the involvement of Oatp1a5 in the pharmacokinetics of NDL may be less than that of celiprolol in rats.