What is the mechanism of action of abacavir (nucleoside reverse transcriptase inhibitor)?

Mechanism of Action of Abacavir

Abacavir is a carbocyclic synthetic nucleoside analogue that inhibits HIV-1 reverse transcriptase by being converted intracellularly to its active metabolite, carbovir triphosphate (CBV-TP), which competes with the natural substrate dGTP and terminates viral DNA chain elongation when incorporated. 1

Pharmacological Pathway

• Abacavir is metabolized intracellularly through cellular enzymes to form carbovir triphosphate (CBV-TP), which is the active metabolite 1, 2
• CBV-TP competitively inhibits HIV-1 reverse transcriptase by:
  • Competing with the natural substrate deoxyguanosine-5'-triphosphate (dGTP) 1
  • Incorporating into viral DNA, where the lack of a 3'-OH group prevents formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation 1
• This mechanism results in termination of viral DNA growth, preventing HIV replication 1, 2

Pharmacokinetic Properties

• Abacavir is rapidly absorbed after oral administration with peak concentrations occurring 0.63-1 hour after dosing 3
• The absolute bioavailability is approximately 83% 3
• Abacavir has a terminal elimination half-life of approximately 1.5 hours in plasma 3
• The active metabolite CBV-TP has a much longer intracellular half-life (>20 hours), which supports once-daily dosing 3

Specificity and Safety Profile

• CBV-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ, which contributes to its selective antiviral activity and relatively low toxicity to human cells 1
• The antiviral activity of abacavir against HIV-1 has been demonstrated in various cell types with EC50 values ranging from 0.07 to 5.8 μM 1
• Abacavir shows activity against different HIV-1 clades (A-G) and HIV-2 isolates 1

Transport Across Blood-CNS Barriers

• Abacavir is a substrate for P-glycoprotein (P-gp), which limits its penetration across the blood-brain barrier 4
• P-gp is the dominant transporter limiting CNS penetration of abacavir 4
• Abacavir is also a substrate for breast cancer resistance protein (BCRP), which may contribute to its directional transport 4
• Despite these transport limitations, abacavir has relatively good CNS penetration compared to other NRTIs 4

Resistance Mechanisms

• Resistance to abacavir develops through specific mutations in HIV-1 reverse transcriptase 1
• Key resistance-associated mutations include:
  • K65R mutation
  • L74V mutation
  • Y115F mutation
  • M184V/I mutation 1
• These mutations can confer cross-resistance to other nucleoside reverse transcriptase inhibitors 1

Clinical Implications

• Abacavir is the only nucleoside analogue that does not require dose modifications for renal insufficiency, making it an attractive option for patients with kidney disease 4
• Before initiating abacavir, HLA-B*5701 testing must be performed to avoid potentially life-threatening hypersensitivity reactions 4
• Abacavir can be used in combination with other antiretroviral agents for effective viral suppression 4, 5

Understanding abacavir's mechanism of action is essential for optimizing its use in antiretroviral regimens and anticipating potential drug interactions or resistance patterns.