Pharmacokinetic and Pharmacodynamic Interaction of Nadolol With Itraconazole, Rifampicin and Grapefruit Juice in Healthy Volunteers

Abstract

To evaluate effects of itraconazole, rifampicin and grapefruit juice on pharmacokinetics and pharmacodynamics of a hydrophilic non-selective β-adrenoceptor blocker nadolol, we conducted an open-label, four-way crossover study in 10 healthy male volunteers. A single oral dose of 30 mg nadolol was administered with water (control), itraconazole (100 mg), or grapefruit juice (300 mL), or after a 6-day pretreatment with rifampicin (450 mg/day). Plasma concentrations and urinary excretions of nadolol were measured over 48 hours after its dosing. Systolic and diastolic blood pressures and pulse rate were periodically recorded after nadolol administration as pharmacodynamic parameters. Itraconazole increased the peak plasma concentration and the area under the plasma concentration-time curve (AUC0-∞ ) of nadolol by 468% and 224% of control, respectively (P < .001). A slight, but not statistically significant, decrease in AUC0-∞ of nadolol was observed in rifampicin and grapefruit juice phases as compared to control. Elimination half-life for nadolol did not differ among the four phases. During itraconazole phase, nadolol reduced pharmacodynamic parameters to a greater extent than the other phases. These results suggest that itraconazole substantially increases the oral availability of nadolol possibly by the inhibition of intestinal P-glycoprotein, whereas grapefruit juice has little effect on nadolol pharmacokinetics.

Demonstrating suitability of the Caco-2 cell model for BCS-based biowaiver according to the recent FDA and ICH harmonised guidelines

“…Based on the calculated ER of 0.3, active transport of oxacillin with PepT1 can be assumed, even though the level of expression is lower in Caco-2 cells when compared to human in-vivo situation. [37] Previous in-vivo and invitro studies suggest that nadolol is a P-gp substrate, [8,52] what is consistent with our results (ER = 3.6). Chlorothiazide interacts with well-expressed efflux transporter ABCG2 [53] (ER = 5.0).…”

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“…The candidate CYP3A inhibitors all produce some degree of inhibition of transport mediated by P-glycoprotein (ABCB1). This is evident from in vitro and experimental studies, as well as clinical DDI studies evaluating enteric uptake, partitioning across the blood-brain barrier, or renal clearance of P-glycoprotein substrates [30,36,[97][98][99][100][101][102][103][104][105][106][107][108][109][110]. For victim drugs that are potential substrates both for metabolism by CYP3A and transport by P-glycoprotein, the outcome of DDI studies using these candidate inhibitors is likely to reflect concurrent inhibition of both CYP3A and P-glycoprotein.…”

Effects of β-Blockers and Tricyclic Antidepressants on the Activity of Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2)

“…In addition, Misaka et al (2014) showed that green tea decreased the C max and AUC of nadolol and their results suggest that the interaction is in part mediated by OATP1A2. In contrast, grapefruit juice, an established inhibitor of OATP1A2, did not have the same effect on nadolol (Misaka et al, 2013). A recent study looking at influx and efflux drug transporters in the small intestine using liquid chromatography-tandem mass spectrometry demonstrated that OATP1A2 was not expressed in any segment of the intestine and other influx transporters, such as OATP2B1, PEPT1, and OCT1, may be implicated in the absorption of drugs instead (Groer et al, 2013;Drozdzik et al, 2014).…”