Tigecycline and cyclosporine interaction—an interesting case of biliary-excreted drug enhancing the oral bioavailability of cyclosporine

Abstract

To the Editor: Stumpf et al. (2009) have reported an interesting observation of enhanced blood levels of cyclosporine in a renal transplant patient upon co-medication with tigecycline [1]. The interaction between the two agents was found to be acute in nature and necessitated a dose reduction of cyclosporine to avoid safety concerns. Upon the cessation of tigecycline treatment, the dosing of cyclosporine had to be restored to its original level to avoid graft rejection due to lower efficacy [1]. The observations made in this case study are important ones since there is a myth that drugs administered through two different routes are less likely to show a pharmacokinetic interaction. Additionally, it provides rational information in our understanding of the issues associated with an intravenously administered drug (tigecycline) versus an orally administered drug (cyclosporine). While the authors have proposed p-glycoprotein (pgp) effux transporters as possible culprits for this pharmacokinetic interaction [1], this communication attempts to bring in additional views for consideration to explain this intriguing phenomenon. Although Stumpf et al. do not report the route of administration of cyclosporine, it is presumed that the renal transplant patient was on a oral dose of cyclosporine [1]. As described by the authors [1], the oral bioavailability of cyclosporine is highly variable owing to the concomitant effects of cytochrome P450 (CYP) metabolism (CYP3A4/ 3A5) and pgp-related efflux transport activity [2]. Upon the addition of tigecyline treatment, there was an acute increase in the blood concentrations of cyclosporine suggesting an enhanced oral bioavailability of cyclosporine [1]. The altered bioavailability of cyclosporine could have been achieved by two different possibilities. Firstly, as described by Stumpf et al., since tigecycline is excreted in bile (almost 59% of the administered dose [3]), it is likely that tigecycline would have impaired pgp-mediated gut efflux of cyclosporine resulting in an increased oral bioavailability. Secondly, as an alternate possibility, since cyclosporine is also known to undergo biliary excretion, perhaps there was a preferential biliary excretion of tigecycline as opposed to cyclosporine (direct competition) and/or inhibition of the biliary excrection of cyclosporine by tigecycline leading to the increased blood concentrations of cyclosporine. However, paradoxically, cyclosporine has been shown to increase the plasma concentrations of mycophenolic glucuronide due to the direct inhibition of its biliary excretion pathway [4]. While the above speculative possibilities could account for the observed enhanced bioavailability of cyclosporine in the presence of tigecylcline, one has to closely evaluate the recently reported data from the interaction study of tigecycline and digoxin [5]. Interestingly, tigecycline failed to show an interaction with digoxin, a well known and widely used probe substrate for pgp-mediated efflux [5]. Therefore, a key question to ask should be why tigecylcine would preferentially affect the pgp efflux of cyclosporine but not digoxin. A recent work published by Igel et al. (2008) sheds some light on the specificity of the involvement of apically located pgp transporters for the absorption and transport of digoxin [6]. The use of a pgp inhibitor such as quinidine in the study effectively increased the absorption of digoxin [6]. However, the bioavailability and oral absorption of antipyrine, which undergoes paracellular absorption, was Eur J Clin Pharmacol (2009) 65:543–544 DOI 10.1007/s00228-009-0631-x