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- Title
Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P‐Glycoprotein.
- Authors
Shimazaki, Sho; Kuroda, Junko; Shimomura, Kenju; Misaka, Shingen
- Abstract
Nadolol is a hydrophilic and nonselective β‐adrenoceptor blocker with a bioavailability of 30%, relatively longer half‐life, negligible metabolism, and predominant renal excretion. Previous studies have reported that nadolol is a substrate of P‐glycoprotein, and the coadministration with itraconazole, a typical P‐glycoprotein inhibitor, results in elevated plasma concentrations and cumulative urinary excretion of nadolol. In this study, we assessed whether measurements of urinary‐excreted nadolol can be an alternative method of plasma pharmacokinetics for P‐glycoprotein‐mediated drug interactions in humans. We reanalyzed the pooled data set of plasma concentration and urinary excretion of nadolol from our previous clinical studies in a total of 32 healthy Japanese adults. The area under the plasma concentration‐time curve from 0 to infinity (AUC0‐∞) of nadolol in individual subjects was significantly correlated with the maximum plasma concentration (r = 0.80, P <.01) and the cumulative amount excreted into urine (Ae) at 4 (r = 0.51, P =.01), 8 (r = 0.63, P <.01), 24 (r = 0.75, P <.01), and 48 (r = 0.77, P <.01) hours. Significant correlations were also observed between the AUC and Ae during the same respective periods. In the drug interactions of nadolol with itraconazole, rifampicin, a well‐known P‐glycoprotein inducer, or grapefruit juice, there were significant correlations between the differences in AUC0‐48 and those in Ae, 0‐48 from the controls in individual subjects. These results suggest that the measurements of urinary excretion of nadolol can be employed as a sensitive and reliable alternative to plasma pharmacokinetics for the evaluation of P‐glycoprotein‐mediated drug interactions.
- Subjects
NADOLOL; IN vivo studies; FRUIT juices; BLOOD plasma; GRAPEFRUIT; DRUG interactions; GLYCOPROTEINS; ITRACONAZOLE; RIFAMPIN
- Publication
Journal of Clinical Pharmacology, 2021, Vol 61, Issue 6, p799
- ISSN
0091-2700
- Publication type
Article
- DOI
10.1002/jcph.1812