An S-warfarin and AZD1981 interaction:in vitroand clinical pilot data suggest the N-deacetylated amino acid metabolite as the primary perpetrator
| Autor: | Clive Brealey, Pär Nordell, Petter Svanberg, Wolfgang Kühn, Barry Jones, Marie Brännström, Ken Grime, Timothy Mant, Rikard Pehrson, Michael Gillen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pharmacology medicine.drug_class Metabolite Primary metabolite Cytochrome P450 Biology Receptor antagonist 030226 pharmacology & pharmacy In vitro Excretion 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry medicine biology.protein Pharmacology (medical) CYP2C9 Drug metabolism |
| Zdroj: | British Journal of Clinical Pharmacology. 83:381-392 |
| ISSN: | 0306-5251 |
| DOI: | 10.1111/bcp.13102 |
| Popis: | Aim AZD1981 is an orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist progressed to phase II trials for the treatment of allergic asthma. Previously performed in vitro human hepatocyte incubations identified N-deacetylated AZD1981 as a primary metabolite. We report on metabolite exposure from a clinical excretion balance, on in vitro studies performed to determine the likelihood of a metabolite-dependent drug–drug interaction (DDI) and on a clinical warfarin DDI study. The aim was to demonstrate that N-deacetylated AZD1981 is responsible for the observed interaction. Methods The excretion and biotransformation of [14C]-AZD1981 were studied in healthy male volunteers, and subsequently in vitro cytochrome P450 (CYP) inhibition and hepatocyte uptake investigations were carried out with metabolites and the parent drug. A clinical DDI study using coadministered twice-daily 100 mg and 400 mg AZD1981 with 25 mg warfarin was performed. Results The excretion balance study showed N-deacetylated AZD1981 to be the most abundant metabolite present in plasma. In vitro data revealed the metabolite to be a weak CYP2C9 time-dependent inhibitor, subject to more active hepatic uptake than the parent molecule. Clinically, the S-warfarin area under the plasma concentration–time curve increased, on average, 1.4-fold [95% confidence interval (CI) 1.22, 1.50] and 2.4-fold (95% CI 2.11, 2.64) after 100 mg (n = 13) and 400 mg (n = 11) AZD1981 administration, respectively. In vitro CYP inhibition and hepatocyte uptake data were used to explain the interaction. Conclusions N-deacetylated AZD1981 can be added to the small list of drug metabolites reported as sole contributors to clinical drug–drug interactions, with weak time-dependent inhibition exacerbated by efficient hepatic uptake being the cause. |
| Databáze: | OpenAIRE |
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