Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor
| Autor: | Jin Chen, Gangadhar Sunkara, Kenneth Kulmatycki, Sam Rebello, Tapan K. Majumdar, Arpine Vapurcuyan, Aishwarya Movva, Atish Salunke, Dan Meyers, Imad Hanna, Adrienne Natrillo |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Organic anion transporter 1 Abcg2 Metabolic Clearance Rate Aminopyridines Organic Anion Transporters Acetates Organic Anion Transporters Sodium-Independent Pharmacology Transfection Risk Assessment Solute Carrier Organic Anion Transporter Family Member 1B3 Young Adult chemistry.chemical_compound Estrone sulfate Cell Line Tumor medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans Drug Interactions Pharmacology (medical) Rosuvastatin Diacylglycerol O-Acyltransferase Rosuvastatin Calcium Sulfonamides Dose-Response Relationship Drug biology Liver-Specific Organic Anion Transporter 1 Membrane Transport Proteins Middle Aged Drug interaction Healthy Volunteers Neoplasm Proteins Fluorobenzenes Dose–response relationship Pyrimidines chemistry Area Under Curve biology.protein ATP-Binding Cassette Transporters Female Efflux Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.drug |
| Zdroj: | Int. Journal of Clinical Pharmacology and Therapeutics. 53:345-355 |
| ISSN: | 0946-1965 |
| Popis: | Objective An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. Methods The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Results Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. Conclusion These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin. |
| Databáze: | OpenAIRE |
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