Assessment of the role of nucleoside transporters, P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2 in the placental transport of entecavir using in vitro, ex vivo, and in situ methods.

The nucleoside analog entecavir (ETV) is a first-line pharmacotherapy for chronic hepatitis B in adult and pediatric patients. However, due to insufficient data on placental transfer and its effects on pregnancy, ETV administration is not recommended for women after conception. To expand knowledge of safety, we focused on evaluating the contribution of nucleoside transporters (NBMPR sensitive ENTs and Na+ dependent CNTs) and efflux transporters, P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance-associated transporter 2 (ABCC2), to the placental kinetics of ETV. We observed that NBMPR and nucleosides (adenosine and/or uridine) inhibited [3H]ETV uptake into BeWo cells, microvillous membrane vesicles, and fresh villous fragments prepared from the human term placenta, while Na+ depletion had no effect. Using a dual perfusion study in an open-circuit setup, we showed that maternal-to-fetal and fetal-to-maternal clearances of [3H]ETV in the rat term placenta were decreased by NBMPR and uridine. Net efflux ratios calculated for bidirectional transport studies performed in MDCKII cells expressing human ABCB1, ABCG2, or ABCC2 were close to the value of one. Consistently, no significant decrease in fetal perfusate was observed in the closed-circuit setup of dual perfusion studies, suggesting that active efflux does not significantly reduce maternal-to-fetal transport. In conclusion, ENTs (most likely ENT1), but not CNTs, ABCB1, ABCG2, and ABCC2, contribute significantly to the placental kinetics of ETV. Future studies should investigate the placental/fetal toxicity of ETV, the impact of drug-drug interactions on ENT1, and interindividual variability in ENT1 expression on the placental uptake and fetal exposure to ETV.

Review of recent studies on resistance to cytotoxic deoxynucleoside analogues.

Cytotoxic deoxynucleoside analogues are widely used in the treatment of haematological malignancies and solid tumours. Their metabolism and mechanisms of action are relatively well known, but with ongoing technological development, a continuous flow of scientific data is constantly adding new knowledge to this field. Thus, what was already a well-developed area some years ago has continued its expansion and become a better understood part of medical sciences. In order to keep abreast of the latest advances on cellular and clinical resistance to deoxynucleoside analogues, we have reviewed the recent literature and provide here an update on the subject. We have particularly focused on changes in gene products involved in the metabolic pathway of these drugs, such as membrane transporters, kinases, deaminases and 5'-nucleotidases. We also gave an overview on the chemical and biological development of modified deoxynucleoside analogues such as conjugates and pronucleotides.