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

Autor: Shimazaki S; Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, Japan., Kuroda J; Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, Japan., Shimomura K; Department of Bioregulation and Pharmacological Medicine, School of Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan., Misaka S; Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, Japan.; Department of Bioregulation and Pharmacological Medicine, School of Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2021 Jun; Vol. 61 (6), pp. 799-805. Date of Electronic Publication: 2021 Jan 29.
DOI: 10.1002/jcph.1812
Abstrakt: 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 (AUC 0-∞ ) 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 (A e ) 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 A e 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 AUC 0-48 and those in A e, 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.
(© 2021, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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