#Doctors in training cyp450 inducer trial

Moreover, altered CYP activity has been observed in inflammatory-associated disease states, including HIV and hepatitis C infection, liver disease and cancer 15, 16, 17, 18, 19, 20, 21.

Evidence for inflammation-induced repression of hepatic CYP expression has been well-established in vitro 11, 12, 13, 14. To date, very little is known about the effects of inflammatory cytokines on CYP activity in cancer patients. However, even after accounting for these known environmental determinants of CYP activity, there remains substantial unexplained variability 8.ДЄdditional factors known to influence the expression and metabolic activity of hepatic CYP enzymes include age, sex, environmental exposures, epigenetic events, use of concurrent medications, and comorbid inflammatory diseases 4. Some environmental influences on phenotype are well described- such as co-administered drugs that inhibit or induce CYP metabolism 8, 10. In particular, CYP phenotypes are not stable over time, indicating environmental factors are affecting phenotype 4. However, large genotypeвЂ“phenotype association studies are inconsistent and at times conflicting 8, 9, demonstrating that genetics is not the sole cause of intra- and inter-individual differences in CYP activity. It has been suggested that differences in chemotherapy metabolism may play a role in regulating response to chemotherapy between patients and within an individual over time 1, 2, 3.Дrug metabolising CYP enzymes can be phenotypically grouped into three distinct subpopulations, extensive metabolisers (EMs), poor metabolisers (PMs) or intermediate metabolizers (IMs), and in the case of CYP2C19 and CYP2D6, ultra-rapid drug metabolisers (UMs) 4, 5, 6, 7. In BC patients, there is high variability in intra- and inter-individual response to chemotherapy and this remains unpredictable at the individual patient level. These agents have narrow therapeutic indices, so even minor changes in CYP expression or activity may have significant impact on drug exposure, potentially impacting efficacy or toxicity 2. Hepatic cytochrome P450 (CYP) drug metabolising enzymes are involved in metabolism of chemotherapy drugs used to treat breast cancer (BC), such as tamoxifen, cyclophosphamide, dexamethasone, doxorubicin and paclitaxel 1, 2.

#Doctors in training cyp450 inducer trial

Future use of phenotyping cocktails in a clinical oncology setting may help guide drug dosing and improve chemotherapy outcomes.Д¬linical Trial Registration: Trial was retrospectively registered to the Australia New Zealand Clinical Trial Registry (ANZCTR). Relative CYP activity varied between participants, particularly for CYP2C9 and CYP2D6, and changes in serum concentrations of the inflammatory cytokine monocyte chemoattractant protein 1 inversely correlated to CYP3A4 activity during chemotherapy. This exploratory single arm open label trial investigated changes in in vivo CYP activity in twelve women treated for stage II or III breast cancer, and demonstrated for the first time the feasibility and safety of utilising the Inje phenotyping cocktail to measure CYP activity in cancer patients receiving chemotherapy. Therefore, better understanding of these biological relationships is required. Cytokine-associated changes in CYP metabolism may alter chemotherapy exposure, potentially affecting treatment response and patient survival. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of many chemotherapy agents, and CYP enzyme activity has been shown to be modified by inflammatory cytokines in vitro and in vivo. Obesity and exercise are associated with better and worse outcomes, respectively, and it is known that both impact the systemic cytokine milieu. Individual response to chemotherapy in patients with breast cancer is variable.