Paclitaxel is an antineoplastic agent which acts by inhibitor of cellular mitosis and which currently plays a central role in the therapy of ovarian, breast, and lung cancer. Therapy with paclitaxel has been associated with a low rate of serum enzyme elevations, but has not been clearly linked to cases of clinically apparent acute liver injury.
Paclitaxel (pak" li tax' el) is a complex diterpenoid molecule that contains a central 8-member taxane ring. Paclitaxel was initially isolated from the bark of the Western Yew tree (Taxus breviflora) and found to have antitumor activity in high throughput assays. It is a potent antineoplastic agent and its mechanism of action appears to be mediated by its binding to microtubulin, which is important in the mitototic phase of cell division. The binding of paclitaxel prevents the disassembly of the cytoskeletal microtubules, preventing cell division and leading to cell death. Paclitaxel was approved for use in the United States in 1992 and it remains an important agent in the therapy of several cancers. Paclitaxel is considered a first line treatment for advanced ovarian carcinoma and is also used in breast cancer and advanced non-small cell lung cancer and AIDS-related Kaposi's sarcoma. Paclitaxel is available in solution for injection (6 mg/mL) generically and under the brand names Taxol and Onxol. Paclitaxel is also available as protein bound particles in a lyphophilized powder for injection under the brand name Abraxane. Paclitaxel is administered intravenously, typically as 3 to 24 hour infusions every three weeks in cycles in combination with other antineoplastic agents. The dose varies by indication and body weight and is reduced in persons with preexisting liver disease. Side effects are common and include diarrhea, nausea, vomiting, mucositis, fatigue, mylagias, skin rash, alopecia, phlebitis, bone marrow suppression, fluid retention, cardiomyopathy, peripheral neuropathy and hypersensitivity reactions.
Paclitaxel has been associated with serum aminotransferase elevations in 7% to 26% of patients, but values greater than 5 times the upper limit of normal (ULN) in only 2% of those receiving the highest doses. Similar rates of alkaline phosphatase elevations and occasional mild bilirubin elevations also occur. The abnormalities are usually asymptomatic, mild and self-limited, rarely requiring dose modification or discontinuation. Paclitaxel has not been linked convincingly to instances of clinically apparent liver injury with jaundice. Because paclitaxel is often given with other antineoplastic agents, liver injury arising during therapy cannot always be reliably attributed to paclitaxel or to other specific agents. Furthermore, paclitaxel in combination with other anticancer agents may be associated with reactivation of hepatitis B, increased risk of opportunistic viral infections, sinusoidal obstruction syndrome or sepsis, any of which can cause liver test abnormalities or clinically apparent liver injury.
Mechanism of Injury
The mild liver injury that arises during therapy is probably due to a direct effect of paclitaxel in inhibiting microtubular function. Paclitaxel is metabolized by the cytochrome P450 system, largely CYP 2C8 and to a lesser extent 3A4.
Outcome and Management
The serum aminotransferase elevations that occur on paclitaxel therapy are usually self-limited and do not require dose modification or discontinuation of therapy. No instances of clinically apparent or severe acute liver injury have been convincingly linked to paclitaxel therapy in the published literature.
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