CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 767

Pgp, and MRP activity is a useful strategy to increase the intracellular concentrations,
the oral bioavailability, and the brain penetration of HIV antiretroviral drug substrates
when given in combination with potent inhibitors of these transporters. Drug-drug
interaction has been described between the anticancer drug irinotecan and the im-
munosuppressive tacrolimus in a patient with hepatocellular carcinoma after liver
transplantation. Concomitant administration of irinotecan and tacrolimus resulted in
increased plasma concentrations of SN-38 and severe diarrhea. 271 The mechanism
of this interaction remains unknown, but as tacrolimus has recently been reported to
inhibit BCRP efficiently in vitro 241 , the inhibition of BCRP may explain, at least in
part, this clinically relevant feature. Other clinically relevant drug-drug interactions
involving the anticancer drug irinotecan and its metabolites have been described, but
as irinotecan displays an extremely complex pharmacokinetics that involves several
metabolizing enzymes and membrane transporters, it is likely that various mecha-
nisms and different transporters are involved in these interactions (see the section
“MRP2”).
Modulation of BCRP activity could also be a useful strategy to modify the phar-
macokinetic property of anthelmintic benzimidazole drugs such as albendazole and
fenbendazole. This is a class of drugs used for the treatment of intestinal luminal par-
asites because they are poorly absorbed from the gut. 272 As the sulfoxide derivatives
of albendazole and fenbendazole can be actively transported by BCRP (but not by
Pgp or MRP2) in vitro, clinical use of efficacious BCRP inhibitors might improve
their oral bioavailability by reducing their intestinal elimination and hepatobiliary
secretion. Therefore, this strategy, resulting in increased plasma levels and duration
of systemic exposure to sulfoxide derivatives of methylcarbamate albendazoles, might
improve the therapeutic efficacy of these compounds against extraintestinal (systemic)
infections. 273

24.2.3. ABCC Family (Multidrug Resistance-Associated Proteins,
MRP1 to MRP9)

MRP1 (ABCC1)

Impact of Polymorphism on Function MRP1 (ABCC1) SNPs have been described
in various ethnic populations, but they are not associated with any known genetic dis-
order or phenotype, or with altered pharmacokinetics or toxicity of substrate drugs,
in particular, irinotecan. 7 , 284 - 288 A mutation of R433S in MRP1 has been identi-
fied and displayed decreased organic anion transport and increased resistance to
doxorubicin. 289 In vitro functional characterization studies have shown that some
MRP1 allelic variants display altered substrate specificity. 289 For this reason we spec-
ulate that some MRP1 variants could be associated with changes in drug disposition,
but further studies are awaited.

Main Substrate Classes (Clinically Applied) MRP1 is primarily an organic anion
transporter. MRP1 can also transport compounds that are conjugated or complexed
to glutathione (GSH), sulfate, glutamate, or glucuronide. 244 , 248 , 290 - 296 In addition,