Treatment of HIV infection in pregnant women; importance of placental drug transporters

Infection of pregnant women with human immunodeficiency virus (HIV) is a specific situation, in which both the mother and her fetus are the targets of pharmacotherapy. The current approach to prevent mother-to-child-transmission of HIV consists of highly active antiretroviral therapy (HAART) which is a combination of at least two nucleoside/nucleotide inhibitors of reverse transcriptase (NRTIs) together with one protease/non-nucleoside reverse transcriptase inhibitor (PI/NNRTI) that affect different steps of viral replication cycle. HAART was shown to successfully decrease the rate of child infection from 20-45 % to less than 1 % (De Cock et al., 2000).

Many of NRTIs/NNRTIs have been shown to interact with both ABC and SCL drug transporters (see Tables 1 and 2); nevertheless, most of these compounds pass the placental barrier relatively easily with cord concentrations reaching similar values to those found in mother (Liebes et al., 1990; Havlir et al., 1995; Bloom et al., 1997; Bawdon, 1998; Mirochnick et al., 1998; Moodley et al., 1998; Musoke et al., 1999; Chappuy et al., 2004; Hirt et al., 2009; Flynn et al., 2011). The role of placental transporters in the fetal exposure of reverse transcriptase inhibitors thus remains questionable.

In contrast, transplacental passage of protease inhibitors is generally very limited with cord-to-mother concentration ratios reaching approximately 0-0.2 for ritonavir, 0-0.1 for lopinavir (Marzolini et al., 2002), and less than 0.3 for nelfinavir, saquinavir, and indinavir (Marzolini et al., 2002; Chappuy et al., 2004; Gedeon and Koren, 2006). This can, at least partly, be explained by affinity of protease inhibitors to placental ABC and/or SLC transporters (Smit et al., 1999; Sudhakaran et al., 2008).

Several antiretroviral drugs have the potency to modulate (inhibit) drug transporters of both ABC and SLC families. For example NRTIs, efavirenz, nevirapine, abacavir and tenofovir disoproxil fumarate have been reported to inhibit P-glycoprotein (Storch et al., 2007); abacavir, nevirapine, and efavirenz were also described to inhibit BCRP (Weiss et al., 2007). Emtricitabine, abacavir, zidovudine, and tenofovir disoproxil fumarate showed efficient inhibition of OCT1, OCT2, and OCT3 (Minuesa et al., 2009). Protease inhibitors, in general, seem to be very potent inhibitors of drug transporters: nelfinavir, ritonavir, lopinavir, saquinavir, amprenavir, indinavir, and atazanavir are potent blockers of P-glycoprotein (Storch et al., 2007; Bierman et al., 2010); lopinavir, nelfinavir, saquinavir, atazanavir, and amprenavir decrease efflux activity of BCRP (Weiss et al., 2007); ritonavir, saquinavir, indinavir, and lopinavir have been shown to inhibit OCT1 and OCT2 (Zhang et al., 2000; Kis et al., 2009). OATP1A2 and/or OATP2B1 transport function can be decreased by lopinavir, ritonavir, saquinavir, indinavir, and nelfinavir (Kis et al., 2009). It can be expected that many other interactions between antiretroviral agents and drug transporters (transport/inhibition) are yet to be revealed.

Drug-drug interactions of antiretrovirals on drug transporters thus represent an important issue for pharmacokinetic/pharmacodynamic modifications of HAART effectiveness. For example, ritonavir is often included in HAART not only for its own antiviral activity, but also for its capacity to inhibit drug efflux by ABC transporters as well as drug metabolism by CYP450 enzymes (Gulati and Gerk, 2009). This inhibition results in higher bioavailability, slower elimination and thus increased concentrations of concomitantly administered drugs. In addition, when administered in pregnant woman, we can speculate that ritonavir may inhibit placental ABC transporters (P‑glycoprotein, BCRP) and, therefore, increase fetal exposure to other HAART components. In clinical trials, it has been demonstrated that co-administration of ritonavir with indinavir results in pharmacokinetic interactions that allow for reduced dosage of both drugs (Hsu et al., 1998). Moreover, as even low-dose ritonavir increases plasma concentrations of co-administered indinavir, this combination has been tested as a new medication scheme in children to increase their adherence to indinavir-containing HAART (Fraaij et al., 2007)(Fraaij et al., 2007). Bousquet and colleagues (2008) demonstrated that combined administration of emtricitabine with tenofovir and efavirenz (Atripla^®) results in higher intracellular concentrations of tenofovir as well as emtricitabine. The authors speculate this phenomenon is, at least partly, caused by inhibition of MRP family of ABC transporters (Bousquet et al., 2008). In another study, Minuesa et al. proposed that inhibition of OCTs mediated by abacavir and zidovudine might have important clinical implications especially with regard to lamivudine pharmacokinetics (Minuesa et al., 2009).

Given the wide spectrum of antiretroviral drugs and their interactions with various drug transporters, it is reasonable to predict that many more drug-drug interactions, either advantageous or disadvantageous during HAART treatment will be revealed in the near future. Proper knowledge of these pharmacological aspects should enable the clinicians to exploit or avoid these interactions in order to achieve adequate drug levels in both maternal and fetal circulations.