Transplacental pharmacotherapy of fetal arrhythmias; importance of placental drug transporters

Most fetal heart arrhythmias occur only transiently and do not present significant risk to the fetus. However, several forms of sustained fetal heart arrhythmias are observed in about 1% of all pregnancies (Villain et al., 1990) with considerable hazard for the fetal development. For example, fetal supraventricular tachycardia may cause intrauterine congestive heart failure with hydrops fetalis which is a potentially life-threatening condition for the unborn (Kleinman et al., 1985). Since the outburst of prenatal diagnostics in the 1980s, the importance of managing fetal arrhythmias has been increasing continuously.

Nowadays, the treatment of fetal arrhythmias usually consists of the transplacental administration of digoxin as the drug of first choice (Maeno et al., 2009). If digoxin fails to achieve conversion to sinus rhythm it is followed by, or combined with, sotalol, flecainide, amiodarone, verapamil or other antiarrhythmic agents (Ito, 2001; Singh, 2004; Lulic Jurjevic et al., 2009). Although transplacental passage of digoxin, flecainide, and amiodarone has been confirmed using the technique of ex vivo perfused human term placenta (Schmolling et al., 2000), in vivo data indicate rather low umbilical cord to maternal plasma drug concentration ratio of these compounds with considerable interindividual variability. In detail, fetal-to-maternal drug concentration ratio ranges between 0.1-0.9 for digoxin, 0.5-0.9 for flecainide (Ito, 2001), 0.1-0.6 for amiodarone (Widerhorn et al., 1987) and 0.1-0.2 for verapamil (Widerhorn et al., 1987). It can be speculated that the low drug concentrations in the fetal umbilical vessels may, at least partly, be caused by placental drug transporters. Indeed, most of the cardiovascular drugs have been described as substrates of one or more drug transporters; digoxin is a well-known substrate of P-glycoprotein and some OATP isoforms, flecainide is a substrate and inhibitor of OCT1, OCT2 and OCT3 and amiodarone is a substrate of OCT1, OCT2, OCT3, MATE1 and MATE2 (for details see comprehensive reviews by (Cascorbi, 2011; Keppler, 2011; Nies et al., 2011)). Similarly, other cardiovascular drugs used in transplacental treatment of fetal arrhythmias, such as verapamil and quinidine, are substrates of various drug transporters (Cascorbi, 2011; Keppler, 2011; Nies et al., 2011) and clinically important pharmacokinetic interactions between cardiovascular drugs, mainly digoxin, have been reported (Nademanee et al., 1984; Kodawara et al., 2002; Lee et al., 2010; Glaeser, 2011). It is thus feasible to assume that drug transporters in the placenta decrease mother-to-fetus transport of these cardiovascular drugs and enable drug-drug interactions.

Several reports have been published in which failed maternal therapy with digoxin alone was followed by combined therapy with amiodarone (Pradhan et al., 2006) or quinidine (Spinnato et al., 1984). These combinations lead to conversion to sinus rhythm and resolution of hydrops. We believe that the improved outcome of combined therapy is not only due to pharmacodynamic potentiation. We assume that co-administration of drugs that are substrates and/or inhibitors of drug transporters (such as P-glycoprotein) may lead to various pharmacokinetic interactions throughout the maternal organs including the placenta: (i) competition for drug efflux transporters within the maternal excretory organs, kidney and liver, that results in inhibition of transporter-mediated drug excretion and subsequent increase in drug concentrations in maternal plasma and (ii) drug interactions on the placental transporters that may result in transporter inhibition and greater drug penetration across the placenta to the fetus. For example, verapamil increases digoxin serum concentrations by inhibiting P-glycoprotein-mediated digoxin excretion; in addition, in the treatment of fetal arrhythmias, co-administered verapamil may enhance digoxin transfer into fetus by blocking placental P‑glycoprotein (Ito, 2001).

Sotalol, on the other hand is a compound with limited affinity to drug transporters; it has been suggested to be a P-glycoprotein substrate, however, with questionable clinical significance (Liu et al., 2012)(Liu et al., 2012). This fact, along with its low protein binding, could be the reason for sotalol being completely transported across the placenta from mother to fetus reaching equal concentrations in maternal and fetal compartments at steady state (O'Hare et al., 1980; Oudijk et al., 2003). In view of transplacental pharmacokinetics, sotalol is a good candidate for transplacental treatment of fetal arrhythmias as its passage across the placenta is rather predictable; indeed, there are indices of its preferred use to digoxin (Shah et al., 2012).