Abacavir is a nucleoside reverse transcriptase inhibitor marketed the treatment of infection with the human immunodeficiency virus type 1 (HIV). [1] Abacavir is a carbocyclic 2′-deoxyguanosine nucleoside analogue. It is metabolised intracellularly to a 2′-deoxyguanosine nucleoside analogue which competitively inhibits HIV reverse transcriptase and terminates proviral DNA chain extension. [2]
[1]. Charneira C, et al. Reactive aldehyde metabolites from the anti-HIV drug abacavir: amino acid adducts as possible factors in abacavir toxicity. Chem Res Toxicol. 2011 Dec 19;24(12):2129-41. [2]. Hervey PS, et al. Abacavir: a review of its clinical potential in patients with HIV infection. Drugs. 2000 Aug;60(2):447-79.
Abacavir (1592U89, ABC) is a powerful nucleoside analog reverse transcriptase inhibitor (NRTI) used to treat HIV and AIDS.[1-3]
In Vitro
Abacavir (ABC) exhibits potent in vitro antiviral activity against wild-type HIV-1 (IC50 4.0 μM, MT-4 cells)[1]. Abacavir induces chromosomal DSBs and thereby kills ATL cells but not non-HTLV-1-infected cells. Once abacavir is incorporated into the cells, it is phosphorylated in a unique stepwise anabolism to be converted to the triphosphated guanine analog carbovir (CBV) and then incorporated into host chromosomal DNA by replicative DNA polymerases, leading to premature termination of DNA replication, collapse of the replication fork, and DSB formation. Abacavir induces S/G2-phase arrest and apoptosis in ED-40515(?) cells, but not in Jurkat cells[2].
In Vivo
Abacavir efficiently inhibits the growth of ATL cell xenografts in NOD/SCID mice[2]. In adults, Abacavir is rapidly absorbed after oral administration, with peak concentrations occurring 0.63-1 hour after dosing. The absolute bioavailability of abacavir is approximately 83%. Abacavir pharmacokinetics are linear and doseproportional over the range of 300-1200 mg/day. The apparent volume of distribution of abacavir after intravenous administration is approximately 0.86 ± 0.15 L/kg, suggesting that abacavir is distributed to extravascular spaces. Binding to plasma proteins is about 50% and is independent of the plasma abacavir concentration. Abacavir is extensively metabolized by the liver; less than 2% is excreted as unchanged drug in the urine. Abacavir is primarily metabolized via two pathways, uridine diphosphate glucuronyltransferase and alcohol dehydrogenase, resulting in the inactive glucuronide metabolite and the inactive carboxylate metabolite. The terminal elimination half-life of abacavir is approximately 1.5 hours. The antiviral effect of abacavir is due to its intracellular anabolite, carbovirtriphosphate (CBV-TP). Abacavir is not significantly metabolized by cytochrome P450 (CYP) enzymes, nor does it inhibit these enzymes[3].
SMILES
OC[C@@H]1C=C[C@H](N2C=NC3=C(NC4CC4)N=C(N)N=C23)C1
靶点
Reverse Transcriptase
动物实验
Cell lines: Jurkat cells; Concentrations: 300 μM; Incubation Time: 48 h; Method: Jurkat cells transfected with control siRNA or siTDP1 are treated with or without 300 μM ABC for 48 hours. MTS assay is conducted.[2]
