These are the bits that are confusing for me (and are part of the same study).
Since minimal plasma concentrations have been achieved, no drug interactions via hepatic metabolism have been reported in peer reviewed literature with oral administration of curcumin. However, significant curcumin concentrations have been achieved with the administration of liposomal curcumin in pre-clinical pharmacokinetic studies in dogs and rats (Data not shown). Curcumin, has exhibited potential for drug interactions in previous
in vitro studies (
12,
13).
In this study, curcumin demonstrated the potential to induce the CYP450 3A4 metabolism pathway at high concentration. This may contribute to the poor bioavailability of curcumin due to the prevalent expression and activity of CYP450 3A4 in the intestinal tract walls. It is currently unknown as to the role intestinal metabolism plays in combination with hepatic metabolism since in humans it has not been possible as of yet to uncouple and study these functions separately (
14). With plasma concentrations in the nanomolar range for oral curcumin, hepatic CYPs would be unaffected. In contrast, the concentrations of curcumin in the intestinal tract after eight to 12 gram daily oral doses is likely to be in the micromolar range. Based upon this study, micromolar concentrations would be associated with induction of CYP3A4 thus decreasing bioavailability. Similarly, administering liposomal curcumin intravenously with concentrations in the micromolar range being achieved, the possible hepatic limited CYP450 3A4 drug interactions should be considered in development of combination chemotherapy regimens.
CYP450-mediated drug interactions can result in decreased activity or increased toxicity of one or both agents used in combination and have to be carefully evaluated in the cancer population. Since the majority of cytotoxic chemotherapy agents administered in the oncology setting have a narrow therapeutic index are, it will be important to evaluate the potential effect of liposomal curcumin in combination with other therapies in the context of CYP450 drug interactions through preclinical
in vivo and/or
ex vivo model experiments.
Both the positive control rifampicin and curcumin induced the CYP3A4 pathway in the ex vivo hepatocyte model. The drug interactions with rifampicin observed in clinical practice are significant and close monitoring for drug interaction in patients on rifampicin is generally recommended.
Hence, patients receiving liposomal curcumin should be monitored closely for drug interaction with substrates of the CYP450 3A4 pathway (Table IV). Because of the short term, concentration dependent induction of CYP450 3A4 observed in the ex vivo model, the clinical significance of this potential interaction with other drugs is unknown and warrants further in vivo evaluation. Is this saying that liposomal curcumin is an inducer of CYP3A4? Forgive my ignorance on this, and I gratefully appreciate any advice / feedback.
