The utility of CYP3A activity endogenous markers for evaluating drug-drug interaction between sildenafil and CYP3A inhibitors in healthy subjects.
CYP3A
Clarithromycin
Drug-drug interaction
Endogenous metabolic marker
Itraconazole
Pharmacokinetics
Sildenafil
Journal
Drug metabolism and pharmacokinetics
ISSN: 1880-0920
Titre abrégé: Drug Metab Pharmacokinet
Pays: England
ID NLM: 101164773
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
received:
30
09
2020
revised:
26
10
2020
accepted:
05
11
2020
pubmed:
22
12
2020
medline:
1
10
2021
entrez:
21
12
2020
Statut:
ppublish
Résumé
Cytochrome P450 (CYP) 3A-related drug-drug interaction (DDI) studies are needed during drug development to determine clinical interaction effects. We aimed to evaluate DDI between sildenafil and two CYP3A inhibitors, clarithromycin and itraconazole, regarding the changes in pharmacokinetics and endogenous markers. An open-label, one-sequence, one-period, two-treatment parallel study was conducted in 32 healthy Korean subjects. Each of 16 subjects were randomly assigned to the clarithromycin and itraconazole groups. Both groups received a single dose of sildenafil 25 mg as a control, and either clarithromycin 250 mg or itraconazole 100 mg was administered four times to inhibit CYP3A activity. Pharmacokinetics of sildenafil showed the similar magnitude of inhibitory effects of the two inhibitors on total CYP3A activity; both inhibitors similarly increased systemic exposure of sildenafil by 2-fold. Urinary 6β-OH-cortisone/cortisone and plasma 4β-OH-cholesterol were significantly decreased after clarithromycin administration but not after itraconazole. A significant correlation between sildenafil CL/F and metabolic markers of CYP3A activity was observed after clarithromycin administration. We confirmed that sildenafil has moderate pharmacokinetic interaction with clarithromycin and itraconazole. Endogenous markers well reflected the CYP3A inhibition of clarithromycin, suggesting possible utility in DDI study with moderate to strong CYP3A inhibition; however, there are limitations in predicting intestinal CYP3A mediated DDI.
Identifiants
pubmed: 33348240
pii: S1347-4367(20)30426-2
doi: 10.1016/j.dmpk.2020.11.003
pii:
doi:
Substances chimiques
Cytochrome P-450 CYP3A Inhibitors
0
Phosphodiesterase 5 Inhibitors
0
Sildenafil Citrate
BW9B0ZE037
CYP3A protein, human
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
Types de publication
Clinical Trial
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
100368Informations de copyright
Copyright © 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest This research was supported by the Mid-Career Researcher Program through a National Research Foundation of Korea grant funded by the Korean government (NRF-2014R1A2A2A01005541).