Inhibition of Intestinal OATP2B1 by the Calcium Receptor Antagonist Ronacaleret Results in a Significant Drug-Drug Interaction by Causing a 2-Fold Decrease in Exposure of Rosuvastatin
| Autor: | Harma Ellens, Liangfu Chen, May Y K Ho, Marta Johnson, Christopher J Matheny, Dipal Patel |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Organic anion transporter 1 Organic Anion Transporters Pharmaceutical Science CHO Cells Pharmacology 030226 pharmacology & pharmacy Intestinal absorption Substrate Specificity 03 medical and health sciences Cricetulus 0302 clinical medicine In vivo medicine Animals Humans Drug Interactions Rosuvastatin Intestinal Mucosa Rosuvastatin Calcium IC50 Aged Cross-Over Studies Dose-Response Relationship Drug Phenylpropionates biology Chemistry Anticholesteremic Agents Multidrug resistance-associated protein 2 nutritional and metabolic diseases Transporter Middle Aged Healthy Volunteers Organic anion-transporting polypeptide HEK293 Cells Intestinal Absorption 030220 oncology & carcinogenesis Indans biology.protein Female Receptors Calcium-Sensing medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 45:27-34 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC50 = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC50 = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans. |
| Databáze: | OpenAIRE |
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