Assessment of CYP3A‐mediated drug–drug interaction potential for victim drugs using an in vivo rat model. (14th August 2013)

• Record Type: Journal Article
• Authors: Rioux, Nathalie; Bellavance, Edith; Bourg, Serge; Garneau, Michel; Ribadeneira, Maria D.; Duan, Jianmin
• Is Part Of: Biopharmaceutics & drug disposition. Volume 34:Number 7(2013:Oct.)
• Page Start: 396
• Page End: 401
• Publication Date: 2013-08-14
• Subjects: Biopharmaceutics -- Periodicals; Drugs -- Metabolism -- Periodicals; Pharmacology -- Periodicals; Biopharmaceutics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615.19
• DOI: 10.1002/bdd.1855
• Languages: English
• ISSNs: 0142-2782

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>The present study aims to determine if an <italic>in vivo</italic> rat model of drug–drug interaction (DDI) could be useful to discriminate a sensitive (buspirone) from a 'non‐sensitive' (verapamil) CYP3A substrate, using ketoconazole and ritonavir as perpetrator drugs. Prior to <italic>in vivo</italic> studies, ketoconazole and ritonavir were shown to inhibit midazolam hydroxylation with IC<sub>50</sub> values of 350 ± 60 n<sc>m</sc> and 11 ± 3 n<sc>m</sc>, respectively, in rat liver microsomes (RLM). Buspirone and verapamil were also shown to be substrates of recombinant rat CYP3A1/3A2. In the rat model, the mean plasma <italic>AUC</italic><sub>0‐inf</sub> of buspirone (10 mg/kg, p.o.) was increased by 7.4‐fold and 12.8‐fold after co‐administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. The mean plasma <italic>AUC</italic><sub>0‐inf</sub> of verapamil (10 mg/kg, p.o.) was increased by 3.0‐fold and 4.8‐fold after co‐administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. Thus, the rat DDI model correctly identified buspirone as a sensitive CYP3A substrate (>5‐fold <italic>AUC</italic> change) in contrast to verapamil. In addition, for both victim drugs, the extent of DDI when co‐administered was greater with ritonavir compared with ketoconazole, in line with their <italic>in vitro</italic> CYP3A inhibition potency in RLM. In conclusion, our study extended the rat DDI model applicability to two additional victim/perpetrator pairs. In addition, we suggest that use of this model would increase our confidence in estimation of the DDI potential for victim drugs in early discovery. Copyright © 2013 John Wiley & Sons, Ltd.</p> </abstract>