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Static Model-Based Assessment of OATP1B1-Mediated Drug Interactions with Preincubation-Dependent Inhibitors Based on Inactivation and Recovery Kinetics
- Source :
- Drug metabolism and disposition: the biological fate of chemicals. 48(9)
- Publication Year :
- 2020
-
Abstract
- Quantitative assessment of drug-drug interactions (DDIs) via organic anion transporting polypeptide (OATP) 1B1 is one of the key issues in drug development. Although OATP1B1 inhibition exhibits unique characteristics, including preincubation dependence for some inhibitors, a limited approach has been attempted based on the static model that considers such preincubation dependence in the prediction of DDIs via OATP1B1. The present study aimed to establish the prediction of DDIs via OATP1B1 using preincubation-dependent inhibitors based on the static model and incorporating both inactivation and recovery of OATP1B1 activity. Cyclosporine A was selected as a preincubation-dependent inhibitor, as well as five substrates that include probes and pharmaceuticals. The inhibition ratio (R value) calculated on the basis of a conventional static model, considering inhibition of OATP1B1 and contribution ratio of OATP1B1 to the overall hepatic uptake, was much lower than the reported AUC ratio, even when IC50 values were estimated after preincubation conditions. Conversely, the R value that was estimated by considering inactivation and recovery parameters was closer to the AUC ratio. The R value that was calculated assuming the complete contribution of OATP1B1 was much higher than the AUC ratio, avoiding false-negative prediction. The R value estimated by considering inactivation and recovery for another combination of a preincubation-dependent inhibitor, asunaprevir, and substrate drug, rosuvastatin, was also closer to the AUC ratio. Thus, R values calculated based on such OATP1B1 kinetics would be potential alternative indexes for the quantitative prediction of OATP1B1-mediated DDIs using preincubation-dependent inhibitors, although this prediction is affected by estimation of the contribution ratio of substrates. SIGNIFICANCE STATEMENT: Static model-based quantitative prediction of organic anion transporting polypeptide 1B1-mediated drug-drug interactions induced by preincubation-dependent inhibitors was newly proposed to avoid false-negative prediction.
- Subjects :
- Drug
media_common.quotation_subject
Kinetics
Drug Evaluation, Preclinical
Pharmaceutical Science
Key issues
030226 pharmacology & pharmacy
Models, Biological
03 medical and health sciences
Inhibitory Concentration 50
0302 clinical medicine
Quantitative assessment
Ic50 values
Humans
Drug Interactions
Rosuvastatin Calcium
media_common
Pharmacology
Sulfonamides
Static model
biology
Chemistry
Liver-Specific Organic Anion Transporter 1
Substrate (chemistry)
Isoquinolines
Recombinant Proteins
Organic anion-transporting polypeptide
Hepatobiliary Elimination
HEK293 Cells
Liver
030220 oncology & carcinogenesis
Area Under Curve
biology.protein
Biophysics
Cyclosporine
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Subjects
Details
- ISSN :
- 1521009X
- Volume :
- 48
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Accession number :
- edsair.doi.dedup.....00dc558025aed36d84775342c1cd5589