Drug Metabolism in Drug Design and Development Basic Concepts and Practice

mL/min by inhibiting P-gp in the liver and kidney and inhibiting metabolizing
enzymes. In a dose escalation study, patients receiving 45 mL/m^2 cremophor
reached plasma levels 1.5mL/mL, a level well tolerated in humans.
Cremophor 45 mL/m^2 over 6 h with 35 mg/m^2 doxorubicin are recommended
for further studies (Millward et al., 1998). Similarly, in a study with 12 health
volunteers, cremophor EL increased digoxin (0.5 mg)Cmaxby 22% and AUC
by 22% (ten Tije et al., 2003).
Although most investigations have focused on formulation effect on P-gp,
formulation may also affect other transporters in the gut and other organs like
liver and kidney. This remains to be explored as more knowledge of other
transporters becomes available.

6.5.6 In vitro–In vivoCorrelation

Prediction of transporter-mediated drug-drug interactions in humans by using
in vitrodata is of great interest. Given the success of predicting CYP-based
drug interactions, Endres et al. proposed to adopt the same approach using the
following equations:

R¼

AUCðinhÞ

AUC

¼

1

fcl

1 þðfu½IŠ=KiÞ

þð 1 fclÞ

ð 6 : 3 Þ

wherefuand [I] are the free fraction and plasma concentration of the inhibitor,
and fcl is the fraction of the total clearance mediated by the affected
transporter. Whenfcl= 1 (transporter-mediated clearance contribution equals
to the total clearance), the Equation 6.3 can be simplify to Equation 6.4
(Endres et al., 2006).

R¼

AUCðinhÞ

AUC

¼ 1 þðfu½ŠI=KiÞð 6 : 4 Þ

Unlike the progress in the predictions of CYP-based DDIs (Lu et al.,
2007;35:79–85), transporter-basedin vitro–in vivocorrelations and predic-
tions of DDI in humans are still in infancy stage. The predicted fold change
in AUC based on Equation 6.3 or 6.4 was not close to every observed case
yet because of multiple transporters and other mechanisms involved in the
drug interactions and the difficulty to estimate the drug concentration at the
site of interactions (Endres et al., 2006). Current FDA draft guidance on
DDI studies recommends anin vivo drug interaction study with a P-gp
substrate such as digoxin if a P-gp inhibitor shows [I]/Kior I/IC 50 higher
than 0.1. However, one shall also consider the overall clearance by
transporters, therapeutic range, frequency of dosing, and therapeutic area
for assessing the need for a DDI study. There is still a lack of understanding
on evaluating quantitatively the role of transporters in overall clearance or
uptake.

TRANSPORTERS IN DRUG–DRUG OR DRUG–FOOD INTERACTIONS 175