Paclitaxel hepatic metabolism

Pharmacokinetics Paclitaxel is infused over 3-4 hours. Hepatic metabolism and biliary excretion are responsible for elimination of paclitaxel. Thus dose modification is not required in patients with renal impairment, but doses should be reduced in patients with hepatic dysfunction. 

PACLITAXEL 1. ANTIBIOTICS-rifampicin 2. ANTIDEPRESSANTS-St John s wort 3. ANTIEPILEPTICS -carbamazepine, phenobarbital, phenytoin 1 plasma concentration of paclitaxel and 1 efficacy of paclitaxel Due to induction of hepatic metabolism of paclitaxel by the CYP isoenzymes Monitor for clinical efficacy and need to T dose if inadequate response is due to interaction... 

After intravenous administration, paclitaxel is extensively distributed, despite extensive binding to plasma proteins (89%), presumably albumin (2). Its routes of elimination have not been fully elucidated, but renal clearance accounts for an insignificant proportion of total systemic clearance, suggesting that metabolism, biliary excretion, or excretion via other routes are responsible for elimination (6). High concentrations of paclitaxel and its hydroxylated metabolites have been found in rat and human bile, suggesting hepatic metabolism (8). In all, 11 metabolites of paclitaxel have been identified, and paclitaxel metabolism to 6-a-hydroxypaclitaxel is an important detoxification pathway (6,9). 

Paclitaxel is administered as a 3-hour infusion of 135-175 mg/rrf every 3 weeks, or as a weekly 1-hour infusion of80-100 mg/m. Longer infusions (96 hours) have yielded significant response rates in breast cancer patients, but this form of treatment has serious practical limitations. The drug undergoes extensive CYP-mediated hepatic metabolism (primarily CYP2C8), and <10% of... 

The routes of elimination of paclitaxel have not been fully established in humans. Only a small proportion of the drug (1.3-13%) is excreted unchanged in the urine [23 j. The main route of elimination appears to be via hepatic metabolism (specifically CYP3A4 and CYP2C8 activity) and biliary clearance. The three major metabolites of paclitaxel are 6n-hydroxy-paclitaxel, 3 -para-hydroxypaclitaxel, and 6a-3 -para-dihydroxypaclitaxel [24 ]. After intravenous administration of paclitaxel, the amounts of each metabolite excreted via the feces were 26%, 2%, and 6% respectively [2 ]. The metabolites of paclitaxel do not have significant cytotoxic properties themselves [25 ]. 

Panday VR, Huizing MT, Willemse PH, De Graeff A, ten Bokkel Huinink WW, Vermorken JB, Beijnen JH. Hepatic metabolism of paclitaxel and its impact in patients with altered hepatic function. Semin Oncol 1997 24(4 Suppl 11) Sll-34-8. 

FIGURE 31.4 High-performance liquid chromatograms comparing in vitro paclitaxel metabolism by hepatic microsomes from rats (dotted line) and humans (solid line). The major human metabolite, designated peak H, was not formed by rats. (Adapted from Jamis-Dow CA, Klecker RW, Katki AG, Collins JM. Cancer Chemother Pharmacol 1995 6 107-14.)... 

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