Altered bile acid and coproporphyrin-I disposition in patients with autosomal dominant polycystic kidney disease.
chronic kidney disease
drug interactions
drug transporters
hepatotoxicity
mass spectrometry
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
24 Sep 2024
24 Sep 2024
Historique:
revised:
22
06
2024
received:
17
12
2023
accepted:
30
07
2024
medline:
25
9
2024
pubmed:
25
9
2024
entrez:
24
9
2024
Statut:
aheadofprint
Résumé
Serum, liver and urinary bile acids are increased, and hepatic transport protein levels are decreased in a non-clinical model of polycystic kidney disease. Similar changes in patients with autosomal dominant polycystic kidney disease (ADPKD) may predispose them to drug-induced liver injury (DILI) and hepatic drug-drug interactions (DDIs). Systemic coproporphyrin-I (CP-I), an endogenous biomarker for hepatic OATP1B function and MRP2 substrate, is used to evaluate OATP1B-mediated DDI risk in humans. In this clinical observational cohort-comparison study, bile acid profiles and CP-I concentrations in healthy volunteers and patients with ADPKD were compared. Serum and urine samples from healthy volunteers (n = 16) and patients with ADPKD (n = 8) were collected. Serum bile acids, and serum and urine CP-I concentrations, were quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Patients with ADPKD exhibited increased serum concentrations of total (1.3-fold) and taurine-conjugated (2.8-fold) bile acids compared to healthy volunteers. Specifically, serum concentrations of six bile acids known to be more hydrophobic/hepatotoxic (glycochenodeoxycholate, taurochenodeoxycholate, taurodeoxycholate, lithocholate, glycolithocholate and taurolithocholate) were increased (1.5-, 2.9-, 2.8-, 1.6-, 1.7- and 2.7-fold, respectively) in patients with ADPKD. Furthermore, serum CP-I concentrations were elevated and the renal clearance of CP-I was reduced in patients with ADPKD compared to healthy volunteers. Increased exposure to bile acids may increase susceptibility to DILI in some patients with ADPKD. Furthermore, the observed increase in serum CP-I concentrations could be attributed, in part, to impaired OATP1B function in patients with ADPKD, which could increase the risk of DDIs involving OATP1B substrates compared to healthy volunteers.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM122576
Pays : United States
Informations de copyright
© 2024 British Pharmacological Society.
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