| Popis: |
Tenofovir, a novel nucleotide analog, belongs to the class of acyclic nucleoside phosphonates. Tenofovir is phosphorylated in situ to the virologically active tenofovir diphosphate. Tenofovir diphosphate inhibits human immunodeficiency virus (HIV-1 and HIV-2) DNA polymerases. Tenofovir exists as a dianion at physiological pH and does not readily undergo passive diffusion across cellular membranes and intestinal mucosa, resulting in low bioavailability after oral administration. A series of novel prodrugs of tenofovir were designed in order to overcome the pharmacokinetic limitations of tenofovir. These prodrugs were engineered to mask the polar phosphonic acid functionality using a novel oxycarbonyloxymethyl linker to allow for passive diffusion across intestinal epithelial cells. Tenofovir disoporxil fumarate was selected as a clinical candidate. After oral administration, the prodrug was readily absorbed and extensively converted to tenofovir. Oral bioavailability of tenofovir from tenofovir disoproxil fumarate 300 mg dose was estimated to be 39% in the fed human subjects. Tenofovir disoproxil fumarate (Viread) has become a pivotal product for treatment of HIV since it was launched in 2001. |
