title: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima, Japan. misaka@fmu.ac.jp
authors.forename: Shingen
authors.initials: S
authors.lastname: Misaka
authors.forename: Nozomu
authors.initials: N
authors.lastname: Miyazaki
authors.forename: Midori S
authors.initials: MS
authors.lastname: Yatabe
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ono
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Shikama
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Fukushima
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D019540:Area Under Curve; D001628:Beverages / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D032083:Citrus paradisi; D018592:Cross-Over Studies; D004347:Drug Interactions; D018565:Food-Drug Interactions; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D017964:Itraconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009248:Nadolol / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D017964:Itraconazole; D009248:Nadolol; D012293:Rifampin