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

Abstract

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, 50 mg/kg) for 30 min before oral administration of NDL (10 mg/kg) significantly increased the area under the plasma concentration-time curve (AUC₀₋∞)of NDL by 1.7-fold compared with control. Intragastric administration of dexamethasone (DEX, 8 mg/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 (C(max)) 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 C(max) and AUC₀₋∞ 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.

Drug–Drug Interactions Involving Dexamethasone in Clinical Practice: Myth or Reality?

“…The role of P-gp has also been emphasized in a study on nadolol, a non-metabolized beta blocker, conducted in rats and showing that dexamethasone, given orally at 8 mg/kg/day for 4 days increased the P-gp levels two-fold in the liver and small intestine, which is consistent with previous findings, and decreased its systemic exposure by one-third, and increased its P gp-mediated renal excretion almost two-fold, which is consistent with a major role of P-gp in the DDI [77]. In rats pretreated with 100 mg/kg/day of dexamethasone given orally for two days, P-gp expression increased two-fold in the intestine, as previously observed, but not in the liver.…”

Renal vectorial transport of berberine mediated by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 (MATE1) in rats

“…Therefore, P‐gp should be responsible for the partial efflux of berberine. Itraconazole, a relatively specific inhibitor of P‐gp (Miyazaki, Misaka, Ogata, Fukushima, & Kimura, ), was used to study the effect on the efflux of berberine. The results showed itraconazole increased the berberine concentration in MDCK‐MDR1 cells in a concentration‐dependent manner, which indicated that itraconazole decreased the efflux of berberine mediated by P‐gp in vitro .…”

Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P‐Glycoprotein

“…10 Moreover, our group previously reported that itraconazole, a typical P-gp inhibitor, significantly increased plasma concentrations and urinary excretion of nadolol in rats and humans probably by inhibiting the efflux transport of nadolol from enterocytes to the intestinal lumen via P-gp. 13,14 In addition, pretreatment with erythromycin, another known P-gp inhibitor, 15 for 2 days prior to nadolol administration resulted in a significant increase in the maximum plasma concentration (C max ) of nadolol in healthy volunteers. 16 Although enzymes and transporters related to nadolol pharmacokinetics in humans are not fully understood, these findings, coupled with nadolol's good safety profile and extensive clinical use for many years, suggest that nadolol can be a possible in vivo phenotyping probe drug for the evaluation of P-gp-mediated DDIs.…”