Dual drug interactions via P-glycoprotein (P-gp)/ cytochrome P450 (CYP3A4) interplay: recent case study of oral atorvastatin and verapamil

Abstract

To the Editor: While drug interaction is an intriguing subject for a clinical pharmacologist/pharmacokineticist, it may be a nightmare for a medical practitioner who needs to juggle dosing adjustments (if applicable) to ensure safety and efficacy so that a co-prescribed therapy is not compromised. In recent years, the concept of dual drug interaction, especially as it relates to P-gp and CYP3A4, has received considerable attention [1–9]. At the outset, it may appear that both P-gp and CYP3A4 are working in tandem to control the oral bioavailability of xenobiotics as they are absorbed through the oral gastrointestinal cavity. However, there may be challenges and complexities to understanding the nature of pharmacokinetic interaction if co-administered compounds have a profound influence on both transporter and enzymatic systems [10–15]. Additionally, the direction and nature of the interaction may further be confounded by physical and/or physiological variants such as food intake, biliary excretion and enterohepatic recycling of the parent/ key metabolites and changes in hepatic blood flow [16–19]. Statins, a well-established class of HMG-CoA reductase inhibitors, provide the fullest scope for understanding the mechanisms governing the dual inhibitory properties that involve the interplay between transport and enzyme systems [18]. Statins can generally be classified into four groups in terms of metabolism preferences within the CYPP450 system: (1) CYP3A4-dependent: atorvastatin and simvastatin, (2) CYP2C9-dependent: fluvastatin, (3) dual CYP (3A4/2C9)-dependent: cerivastatin, and (4) metabolically stable: pravastatin and pitavastatin. However, regardless of metabolism preferences, transport appears to be important for all statins. In addition to P-gp’s involvement in the efflux phenomenon, hepatic uptake transporter may play an important role in its efficacy as well as in clearance mechanisms [18]. Therefore, it is not surprising that statins are compounds of choice for evaluating dual drug-drug interaction potential with the CYP3A4 enzymatic system and Pgp transport system. In a recently published study, Choi et al. (2008) demonstrated a significant single-dose pharmacokinetic interaction between verapamil and atorvastatin in healthy subjects. Therefore, atorvastatin could hinder the formation of norverapamil, an active metabolite of verapamil, due to the potential inhibition of CYP3A4 isozyme. Additionally, it could further enhance the oral bioavailability of verapamil by sufficiently inhibiting the P-gp efflux pump. Based on the data presented in the paper, it appeared that P-gp inhibition could possibly play a greater role than CYP3A4 inhibition because the extent of exposure to norverapamil was virtually unchanged between the two treatments (250±62 ng·h/mL without atorvastatin vs. 265±49 ng·h/mL with atorvastatin) [1]. One must agree, however, with the authors’ interpretation for the considerable decrease in the metabolic ratio (exposure of norverapamil:exposure of verapamil) with atorvastatin treatment; they believed it was primarily driven by an increase in verapamil exposure as opposed to reduced formation of norverapamil [1]. However, no pharmacokinetic data were gathered in this report to evaluate if the kinetics/ disposition of atorvastin and/or its metabolites changed after the co-administration of verapamil [1]. Previously, it was shown that verapamil co-administration enhances the exposure of simvastatin, presumably by its inhibitory effects on both CYP3A4 and P-gp [20]. As verapamil itself is a widely studied substrate because it can Eur J Clin Pharmacol (2008) 64:1135–1136 DOI 10.1007/s00228-008-0512-8