The use of complementary and alternative medicines (CAM) by cancer patients is 
increasing. Concomitant use of CAM and anticancer drugs could lead to serious 
safety issues in patients. CAM have the potential to cause pharmacokinetic 
interactions with anticancer drugs, leading to either increased or decreased 
plasma levels of anticancer drugs. This could result in unexpected toxicities or 
a reduced efficacy. Significant pharmacokinetic interactions have already been 
shown between St. John's Wort (SJW) and the anticancer drugs imatinib and 
irinotecan. Most pharmacokinetic CAM-drug interactions, involve drug 
metabolizing cytochrome P450 (CYP) enzymes, in particular CYP3A4. The effect of 
CAM on CYP3A4 activity and expression can be assessed in vitro. However, no data 
have been reported yet regarding the relevance of these in vitro data for the 
prediction of CAM-anticancer drug interactions in clinical practice. To address 
this issue, a literature research was performed to evaluate the relevance of in 
vitro data to predict clinical effects of CAM frequently used by cancer 
patients: SJW, milk thistle, garlic and Panax ginseng (P. ginseng). Furthermore, 
in clinical studies the sensitive CYP3A4 substrate probe midazolam is often used 
to determine pharmacokinetic interactions. Results of these clinical studies 
with midazolam are used to predict pharmacokinetic interactions with other drugs 
metabolized by CYP3A4. Therefore, this review also explored whether clinical 
trials with midazolam are useful to predict clinical pharmacokinetic 
CAM-anticancer drug interactions. In vitro data of SJW have shown CYP3A4 
inhibition after short-term exposure and induction after long-term exposure. In 
clinical studies using midazolam or anticancer drugs (irinotecan and imatinib) 
as known CYP3A4 substrates in combination with SJW, decreased plasma levels of 
these drugs were observed, which was expected as a consequence of CYP3A4 
induction. For garlic, no effect on CYP3A4 has been shown in vitro and also in 
clinical studies garlic did not affect the pharmacokinetics of both midazolam 
and docetaxel. Milk thistle and P. ginseng predominantly showed CYP3A4 
inhibition in vitro. However, in clinical studies these CAM did not cause 
significant pharmacokinetic interactions with midazolam, irinotecan, docetaxel 
and imatinib. Most likely, factors as poor pharmaceutical availability, 
solubility and bioavailability contribute to the lack of significant clinical 
interactions. In conclusion, in vitro data are useful as a first indication for 
potential pharmacokinetic drug interactions with CAM. However, the discrepancies 
between in vitro and clinical results for milk thistle and P. ginseng show that 
clinical studies are required for confirmation of potential interactions. At 
last, midazolam as a model substrate for CYP3A4, has convincingly shown to 
correctly predict clinical interactions between CAM and anticancer drugs.