Evaluation of the drug–drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transporters
| Autor: | Suresh K. Balani, Mitsuhiro Nishihara, Diane Ramsden |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
CYP3A4 Carbonyl Reductase biology Chemistry CYP3A medicine.drug_class Health Toxicology and Mutagenesis Cytochrome P450 General Medicine Reductase Toxicology Receptor antagonist 030226 pharmacology & pharmacy Biochemistry Organic anion-transporting polypeptide 03 medical and health sciences 0302 clinical medicine Dopamine receptor D3 030220 oncology & carcinogenesis biology.protein medicine |
| Zdroj: | Xenobiotica. :1-12 |
| ISSN: | 1366-5928 0049-8254 |
| DOI: | 10.1080/00498254.2021.1912438 |
| Popis: | Trazpiroben (TAK-906), a peripherally selective dopamine D2/D3 receptor antagonist, is being developed for the treatment of patients with gastroparesis. The potential of trazpiroben to act as a perpetrator or a victim for cytochrome P450 (CYP)- or transporter- mediated drug-drug interactions (DDIs) was evaluated following the latest regulatory guidelines.In vitro studies revealed that trazpiroben is metabolised mainly through a non-CYP pathway (56.7%) by multiple cytosolic, NADPH-dependent reductase, such as aldo-keto reductase and short-chain dehydrogenase/reductase including carbonyl reductases. Remaining metabolism occurs through CYP3A4 and CYP2C8 (43.3%). Trazpiroben is neither an inhibitor nor an inducer of major CYP enzymes at a clinically relevant dose. It is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/1B3, but is not an inhibitor of transporters listed in the DDI guidelines at a clinically relevant dose. This is consistent with findings from CYP3A and P-gp-based clinical assessment showing no substantial change (≤2-fold) in trazpiroben exposure when co-administered with itraconazole.Collectively, trazpiroben has low potential of enzyme-mediated DDIs and is unlikely to act as a perpetrator of transporter-mediated DDIs but there may be a potential to act as a victim of OATP1B1/1B3 DDI that will be evaluated clinically. |
| Databáze: | OpenAIRE |
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