Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing.
BACKGROUND
The inability to accurately predict treatment outcomes for cancer patients in terms of tumour response and anticancer drug toxicity is a severe limitation inherent in current approaches to chemotherapy. Many anticancer drugs are metabolically cleared by cytochrome P450 3A4 (CYP3A4), the predominant CYP expressed in liver. CYP3A4 expression exhibits marked interindividual variation and is repressed in acute inflammatory states.


OBJECTIVE
(1) To review the relevance of CYP3A4 variability to drug metabolism in the setting of cancer and to understand how inflammation associated with malignancy contributes to both this variability and to adverse treatment outcomes. (2) To examine the relationship between tumour-induced inflammation and repression of CYP3A4 and to explore methods of dosing of anticancer drugs in the setting of advanced cancer.


METHODS
Review of relevant literature covering both human and animal studies as well as in vitro mechanistic studies.


CONCLUSIONS
Interindividual variability in CYP3A4 expression is a major confounding factor for effective cancer treatment and methods to predict CYP3A4-mediated drug clearance may have clinical utility in this setting. Although acute inflammation has long been recognised to repress drug metabolism, it is now becoming apparent that cancer patients exhibiting clinical and laboratory features of an inflammatory response have reduced expression of CYP3A4 and possibly other genes relevant to anticancer drug disposition.
Kacevska
Marina
M
University of Sydney, Storr Liver Unit, Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.
Robertson
Graham R
GR
Clarke
Stephen J
SJ
Liddle
Christopher
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D010597:Pharmacogenetics
D000970:Antineoplastic Agents; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human