CLINICAL PHARMACOLOGY

Mechanism of Action

Pentostatin is a potent transition state inhibitor of the enzyme adenosine deaminase (ADA). The greatest activity of ADA is found in cells of the lymphoid system with T-cells having higher activity than B-cells, and T-cell malignancies having higher ADA activity than B-cell malignancies. Pentostatin inhibition of ADA, particularly in the presence of adenosine or deoxyadenosine, leads to cytotoxicity, and this is believed to be due to elevated intracellular levels of dATP which can block DNA synthesis through inhibition of ribonucleotide reductase. Pentostatin can also inhibit RNA synthesis as well as cause increased DNA damage. In addition to elevated dATP, these mechanisms may also contribute to the overall cytotoxic effect of pentostatin. The precise mechanism of pentostatin's antitumor effect, however, in hairy cell leukemia is not known.

Pharmacokinetics/Drug Metabolism

A tissue distribution and whole-body autoradiography study in the rat revealed that radioactivity concentrations were highest in the kidneys with very little central nervous system penetration.

In man, following a single-dose of 4 mg/m2 of pentostatin infused over 5 minutes, the distribution half-life was 11 minutes, the mean terminal half-life was 5.7 hours, the mean plasma clearance was 68 mL/min/m2, and approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. The plasma protein binding of pentostatin is low, approximately 4%.

A positive correlation was observed between pentostatin clearance and creatinine clearance (CLcr) in patients with CLcr values ranging from 60 mL/min to 130 mL/min.1 Pentostatin half-life in patients with renal impairment (CLcr <50 mL/min, n=2) was 18 hours, which was much longer than that observed in patients with normal renal function (CLcr >60 mL/min, n=14), about 6 hours.