Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy.
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Murakami E, Wang T, Park Y, Hao J, Lepist EI, Babusis D, Ray AS
Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy.
Antimicrob Agents Chemother. 2015;59(6):3563-9. doi: 10.1128/AAC.00128-15. Epub 2015 Apr 13.
- PubMed ID
- 25870059 [ View in PubMed]
- Abstract
Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) currently in clinical evaluation for treatment for HIV and hepatitis B virus (HBV) infections. Since the target tissue for HBV is the liver, the hepatic delivery and metabolism of TAF in primary human hepatocytes in vitro and in dogs in vivo were evaluated here. Incubation of primary human hepatocytes with TAF resulted in high levels of the pharmacologically active metabolite tenofovir diphosphate (TFV-DP), which persisted in the cell with a half-life of >24 h. In addition to passive permeability, studies of transfected cell lines suggest that the hepatic uptake of TAF is also facilitated by the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively). In order to inhibit HBV reverse transcriptase, TAF must be converted to the pharmacologically active form, TFV-DP. While cathepsin A is known to be the major enzyme hydrolyzing TAF in cells targeted by HIV, including lymphocytes and macrophages, TAF was primarily hydrolyzed by carboxylesterase 1 (CES1) in primary human hepatocytes, with cathepsin A making a small contribution. Following oral administration of TAF to dogs for 7 days, TAF was rapidly absorbed. The appearance of the major metabolite TFV in plasma was accompanied by a rapid decline in circulating TAF. Consistent with the in vitro data, high and persistent levels of TFV-DP were observed in dog livers. Notably, higher liver TFV-DP levels were observed after administration of TAF than those given TDF. These results support the clinical testing of once-daily low-dose TAF for the treatment of HBV infection.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Tenofovir P-glycoprotein 1 Protein Humans NoSubstrateDetails Tenofovir alafenamide P-glycoprotein 1 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details
