Efflux Transporter‐Mediated Interactions With Atorvastatin—Interesting Findings With Multiple Substrates: Istradefylline, Verapamil, and Rifampicin

I currently under development for a potential treatment of Parkinson disease, is an interesting compound from a clinical pharmacology perspective because it can be classified as a dual inhibitor of cytochrome P450 3A4 and P-glycoprotein. The dynamics of the dual interplay in the modulation of CYP3A4/efflux transporters (ie, P-glycoprotein and others) has been documented extensively. In an interesting study, Rao et al evaluated the pharmacokinetic disposition of atorvastatin following a single-dose administration in healthy participants who had reached steady-state levels of istradefylline after repeated dosing. Although the interaction liability, if any, on the pharmacokinetic disposition parameters of istradefylline by the coadministered atorvastatin was not evaluated, the reported data on atorvastatin suggested a potential drug-drug interaction when the 2 agents were coadministered. Interestingly, the data supported the likely role of the transporter system (presumably P-glycoprotein inhibition) rather than CYP3A4 inhibition of atorvastatin by the steady-state levels of istradefylline, as evidenced by the metabolite data (orthoand para-hydroxyl atorvastatin), which showed minimal to no changes in the exposure data. In summary, the exposure of atorvastatin increased by over 50% in this study, with no alterations in the elimination kinetics of atorvastatin, suggesting that bioavailability of atorvastatin was altered upon coadministration with istradefylline. A few recently reported pharmacokinetic investigations are discussed in this note so that the interplay between CYP3A4/efflux transporter systems (P-glycoprotein) can be better appreciated. In totality, these data aim to provide better perspectives of the drug-drug interactions observed with atorvastatin, an important agent for treating cardiovascular risk factors, which may depend on the type of interacting substrate (verapamil, rifampicin, sildenafil, and/or istradefylline). Choi et al evaluated the potential drug-drug interaction between atorvastatin and verapamil following a single-dose administration of the 2 agents in healthy human volunteers. Here again, the CYP3A4/Pglycoprotein dual interplay exhibited by both atorvastatin and verapamil made this clinical study very interesting from both a mechanistic perspective and a clinical pharmacology point of view. As the study evaluated the pharmacokinetics of verapamil and its active metabolite, norverapamil, it was unknown if verapamil/norverapamil would have perhaps altered the pharmacokinetic disposition of atorvastatin and/ or its key metabolites. However, literature data confirmed that verapamil altered the pharmacokinetics of simvastatin likely by the CYP3A4 inhibitory pathway exhibited by verapamil. Interestingly, following a mere single-dose administration, atorvastatin increased the exposure of verapamil by greater than 40%, suggesting that CYP3A4 isozyme and/or P-glycoprotein inhibition are likely culprits for the observed increase in verapamil’s exposure. However, CYP3A4’s inhibitory role of atorvastatin was readily discounted because the exposure of norverapamil (formation mediated by CYP3A4 isozyme) remained unaltered between verapamil given alone versus verapamil + atorvastatin combined treatment. Another recent work of Lau et al showed how another substrate that has the potential for dual CYP3A4/ efflux transporter interplay such as rifampicin has the potential to alter the pharmacokinetics of atorvastatin at a single-dose administration itself. In this study, the hepatic uptake of atorvastatin was blocked by the effective inhibition of the organic anion transporter pathway (OAT1B1) by rifampicin after a Submitted for publication September 2, 2008; revised version accepted October 15, 2008. Address for correspondence: Nuggehally R. Srinivas, PhD, FCP, Global Drug Development, ClinTec (India) International Pvt Ltd, 3rd Floor, ‘A’ Wing, Divyasree Chambers, Langford Road, Bangalore 560 025, India; e-mail: nsrinivas@clintec.com.