Drug Metabolism in Drug Design and Development Basic Concepts and Practice

TABLE 6.3 (

Continued

)

Substrate

Inhibitor

Inducer

Result

Possible interacting protein

Reference

Docetaxel

Cyclosporin A



Increase in AUC

(7.3-fold), increasein bioavailability(8% to 90%)

P-gp, CYP3A4

Malingre et al. (2001b)

Docetaxel

R101933



Decrease in fecal

excretion(8.47%–0.45%)

P-gp

van Zuylen et al. (2000)

Doxorubicin

GF120918



No change in AUC

and renal clearance

Sparreboom et al. (1999)

Doxorubicin

Cyclosporine



Increase in AUC (1.8-fold),

decrease in total clearance(

37%), no change

in

t1/2

, decrease in

the ratio of AUCof metabolites to thatof parent drugs (



75%)

P-gp, CYP3A4

Rushing et al. (1994)

Doxorubicin

(Adriamycin)

Verapamil



Increase in AUC

(2.0-fold)

P-gp, CYP3A4

Kerr et al. (1986)

Doxorubicin

(Adriamycin)

Cremophor



Increase in AUC

(+23%)

P-gp

Millward et al. (1998)

Etoposide

Cyclosporin A



Decrease in total

clearance (



46%),

renal clearance (



38%)

and nonrenal clearance(

52%)

P-gp, CYP3A4

Lum et al. (1992)

164