MDR1-type P-gp has been shown to transport a variety of drugs including vinca alkaloids, cyclosporin, colchicine, tacrolimus, anthracyclines, etoposide, verapamil, diltiazem, nifedipine, propafenone, digoxin, chloroquine and protease inhibitors, including saquinavir, ritonavir and nelfinavir. There is still debate about dideoxynucleosides such as zidovudine and dideoxyinosine.
There is in vitro and in vivo evidence that drug interactions may occur either due to competition for, inhibition of, or induction of P-gp. Serum digoxin levels may be increased due to reduced renal secretion of digoxin via P-gp interactions with quinidine, verapamil, clarithromycin, propafenone and cyclosporin. Cyclosporin may also lead to increased etoposide levels.
Tacrolimus concentrations may be raised by diltiazem and reduced by rifampin. Early evidence suggests that P-gp activity and expression can be affected by a variety of drugs including calcium channel blockers and immunomodu-lators. It is an interesting point that many of these unrelated compounds are also substrates for cytochrome P450 (CYP) 3A4. Grapefruit juice, naringin and naringenin, known inhibitors of CYP3A4, also appear to have an effect on P-gp. The inhibition of P-gp mediated vinblastine efflux by grapefruit juice components has been reported. Grapefruit juice components appear to inhibit P-gp to the same degree as CYP3A4. Table 6 provides a list of drugs that are cleared by P-gp, but that do not seem to affect other Canadian drugs. Table 7 lists agents that can induce P-gp. Tables 8 and 9 list agents that can inhibit P-gp. The drugs in Table 9 appear to inhibit P-gp but are not believed to be substrates of it.
TABLE 6 P-glycoprotein substrates
TABLE 7 P-glycoprotein inducers
AnthracyclinesDexamethasoneDoxorubicinPhenothiazidesSt John’s wortPrazosinProgesterone
TABLE 9 P-glycoprotein inhibitors (not subtrates)
|Clarithramycin Ketoconazole Local anaesthetics Megestrol acetate Progesterone Reserpine RU486 Testosterone|
TABLE 8 P-glycoprotein inhibitor substrates
AmiodaroneAmitriptylineAtorvastatinCalcium channel blockers*ChlorpromazineCyclosporinDaunorubicin
*Calcium channel blockers implicated include: diltiazem, felodipine, nifedipine, and nicardipine; fFluroquinolones implicated include: ciprofloxacin, enoxacin, norfloxacin