A patient with CML is being treated with imatinib. With this particular drug you should anticipate which of the following? (AIPG 2012)
|A||A high rate of therapeutic failure, and the need to switch to interferons α-2a and –2b|
|B||Hypotension and hypovolemia due to significant drug-induced diuresis|
|C||Interactions with other drugs that depends on or affect the cytochrome P450 system|
|D||Significant toxicity to normal host cells due to profound inhibition of tyrosine kinase|
a. One of several problems with imatinib therapy is that it is a substrate and rather powerful inhibitor of several cytochromes (CYP3A4, 2C9, and 2D6), which are important for the metabolism of many other drugs— warfarin, theophylline, and many others—whose actions can be increased excessively if dosages are not adjusted accordingly. Conversely, imatinib is a target of interactions by this mechanism.
b. Phenytoin, carbamazepine, barbiturates, and rifampin are examples of drugs that can induce imatinib metabolism and reduce the clinical response to it; and such drugs as azole antifungals and erythromycin can reduce imatinib’ s clearance and increase the risk of toxicity.
c. Hypotension and hypovolemia are not what one would expect with this drug. Rather, we see a rather high incidence of fluid retention that may not only affect blood pressure, but also cause such other problems as ascites, pericardial and pleural effusions, and possibly pulmonary edema.
d. Likewise, thrombocytosis is the opposite of what typically occurs: thrombocytopenia and bleeding problems, plus neutropenia and an increased risk of infection are fairly common.
e. Chronic myelogenous leukemia cells synthesize an abnormal constitutively active tyrosine kinase (Bcr-Abl) that is involved in (abnormal) protein phosphorylation. It is that aberrant tyrosine kinase—not ones found in normal host cells—that is affected by the drug and that confers selectivity for the drug’s actions. Thus, tyrosine kinase inhibition does not seem to account for the adverse effects of this drug on host cells.