From the Guidelines
The most likely metabolite affected by hydroxyurea in this case is PRPP (phosphoribosyl pyrophosphate). Hydroxyurea is used in sickle cell disease to increase fetal hemoglobin production, but it also inhibits ribonucleotide reductase, an enzyme critical for DNA synthesis, as noted in the context of its use for modifying the disease course in patients with sickle cell disease 1. This inhibition affects rapidly dividing cells, particularly in bone marrow, leading to decreased production of all blood cell types (pancytopenia), a potential adverse effect that necessitates monitoring of CBC and reticulocyte count every 1 to 3 months depending on the duration of medication use and stability of the dose 1. PRPP is essential for purine and pyrimidine nucleotide synthesis, which are building blocks for DNA and RNA. When hydroxyurea disrupts this pathway by inhibiting ribonucleotide reductase, it prevents the conversion of ribonucleotides to deoxyribonucleotides, affecting PRPP utilization and ultimately reducing blood cell production. This explains why the patient experienced reduced levels of most blood cell types, requiring temporary discontinuation of the medication to allow blood counts to recover. Key points to consider in the management of hydroxyurea-induced myelosuppression include:
- Regular monitoring of blood counts to detect early signs of myelosuppression
- Adjustment of hydroxyurea dosage based on blood count results to minimize the risk of severe myelosuppression
- Temporary discontinuation of hydroxyurea if myelosuppression occurs, as was done in this case, to allow for recovery of blood cell production.
From the FDA Drug Label
The FDA drug label does not answer the question.
From the Research
Hydroxyurea Treatment and Metabolite Synthesis
The patient's reduced blood cell count after hydroxyurea treatment can be attributed to the drug's ability to alter the synthesis of certain metabolites.
- The correct answer is: PRPP (Phosphoribosyl pyrophosphate)
- Hydroxyurea inhibits the enzyme ribonucleotide reductase, which is involved in DNA synthesis 2, 3.
- Ribonucleotide reductase is responsible for converting ribonucleotides to deoxyribonucleotides, a crucial step in DNA replication.
- PRPP is a precursor to ribonucleotide synthesis and is affected by hydroxyurea's inhibition of ribonucleotide reductase.
- The other options, N10-methyl THF, phosphoribosylamine, AMP, and dUDP, are not directly related to the mechanism of hydroxyurea's effect on blood cell count.
- Studies have shown that hydroxyurea treatment can lead to reversible cytopenias, including neutropenia and thrombocytopenia, in patients with sickle cell disease 4.
- The exact mechanism of hydroxyurea's effect on blood cell count is complex and may involve multiple factors, including oxidative stress and DNA damage 3.