Transport of ribavirin across the rat and human placental barrier: Roles of nucleoside and ATP-binding cassette drug efflux transporters.

Ribavirin is a broad-spectrum nucleoside-derived antiviral drug used in combination pharmacotherapy treatment of hepatitis C virus infection. Current evidence indicates that ribavirin-associated teratogenicity is not significant in humans, but more information about the developmental toxicity and mechanisms involved in ribavirin placental kinetics is required to assure its safe use in pregnancy. Thus, we have investigated potential roles of equilibrative nucleoside transporters (ENTs, SLC29A), Na+-dependent influx-mediating concentrative nucleoside transporters (CNTs, SLC28A), and ATP-binding cassette (ABC) efflux pumps, in ribavirin placental pharmacokinetics. Our data indicate that ENT1 participates in uptake of ribavirin by BeWo cells, fresh human placental villous fragments and microvillous plasma membrane (MVM) vesicles while activity of CNTs (probably CNT2) was only observed in BeWo cells. In situ dual perfusion experiments with rat term placenta in an open circuit setup showed that ENT inhibition significantly decreases total ribavirin maternal-to-foetal and foetal-to-maternal clearances. In contrast, no contribution of ABC transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), or multidrug resistance-associated protein (ABCC2) was detected in assays with MDCKII cells overexpressing them, or in closed circuit dual perfusion experiments with rat term placenta. In summary, our data show that ribavirin placental pharmacokinetics are largely controlled by ENT1 activity and independent of ABCB1, ABCG2, and ABCC2 efflux pumps.

Role of nucleoside transporters in transplacental pharmacokinetics of nucleoside reverse transcriptase inhibitors zidovudine and emtricitabine.

INTRODUCTION: Zidovudine (AZT) and emtricitabine (FTC) are effective and well tolerated antiretroviral drugs, routinely used in the prevention of perinatal HIV transmission. However, precise mechanism(s) involved in their transfer from mother to fetus are not fully elucidated. Since both drugs are nucleoside analogues, we hypothesized that the mechanisms of their transplacental passage might include equilibrative nucleoside transporters, ENT1 and/or ENT2. METHODS: To address this issue, we performed in vitro accumulation assays in the BeWo placental trophoblast cell line, ex vivo uptake studies in fresh villous fragments isolated from human placenta and in situ dually perfused rat term placenta experiments. RESULTS: Applying this complex array of methods, we did not prove that ENTs play a significant role in transfer of AZT or FTC across the placenta. DISCUSSION: We conclude that the transplacental passage of AZT and FTC is independent of ENTs. Disposition of either compound into the fetal circulation should thus not be affected by ENT-mediated drug-drug interactions or placental expression of the transporters.

Antimycobacterial 3-aryl-2H-1,3-benzoxazine-2,4(3H)-diones.

A series of 153 derivatives of 3-phenyl-2H-benzoxazine-2,4(3H)-dione substituted in position 6 or 7 on benzoxazine and on the phenyl ring was synthesized. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. The activity of the compounds increases with increasing hydrophobicity and electron-withdrawing properties of the substituents on the phenyl ring, whereas the effect of the substituents on the benzoxazine ring seems to be more complex.

In vitro antifungal activity of 3-phenyl-2H-benzoxazine-2,4(3H)-diones.

A series of 81 3-phenyl-2H-benzoxazine-2,4(3H)-diones with substitution at C(6) on the benzoxazine ring and on the phenyl moiety was synthesized; the compounds were evaluated for antifungal activity against five strains of potentially pathogenic fungi (Absidia corymbifera, Aspergillus fumigatus, Candida albicans, Microsporum gypseum and Trichophyton mentagrophytes). Structure-activity relationships against T. mentagrophytes and M. gypseum were determined using the Free-Wilson method, which was further combined with the approach of Hansch. In vitro antifungal activity becomes higher with increasing electron-accepting ability of the substituents on the phenyl ring, and with increasing lipophilicity.