Zidovudine and Ursodeoxycholic Acid Conjugation: Design of a New Prodrug Potentially Able To Bypass the Active Efflux Transport Systems of the Central Nervous System

We have synthesized a new prodrug obtained by the 5'-ester conjugation of zidovudine (AZT), an antiviral agent substrate of active efflux transport systems (AET), with ursodeoxycholic acid (UDCA), a bile acid able to permeate into the central nervous system (CNS). We have demonstrated, by HPLC analysis, that UDCA-AZT is quickly hydrolyzed in rat plasma and whole blood (half-life <10 s). The same compound was hydrolyzed with slower rates in human plasma (half-life =7.53 +/- 0.44 h) and whole blood (half-life =3.71 +/- 0.16 h), allowing to control the AZT release. UDCA-AZT appeared hydrolyzed also in rat brain (half-life = 7.24 +/- 0.45 min) and liver homogenates (half-life = 2.70 +/- 0.14 min). In the aim to study the permeation properties of the UDCA-AZT across physiological barriers, we have used an established human retinal pigment epithelium (HRPE) cell line to obtain a polarized cell monolayer showing epithelial features. The bidirectional permeation of 30 mu M AZT across this monolayer was regulated by apparent permeability coefficients (P-E) higher from the apical to basolateral compartments (P-E = 209 +/- 4 X 10(-5) cm/min) than in the opposite way (P-E = 133 +/- 8 X 10(-5) cm/min), in conformity with the in vivo behavior of AZT, actively effluxed from the CNS. The influx (P-E = 39.1 +/- 1.2 X 10(-5) cm/min) and efflux (P-E = 31.3 +/- 3.6 X 10(-5) cm/min) permeability coefficients of 30 mu M UDCA-AZT were instead the same, suggesting the ability of the pro drug to avoid the AET systems and, potentially, to allow its accumulation in the CNS. The relatively low P-E values of UDCA AZT were associated with a partial hydrolysis during its permeation across the cell monolayer.