CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 748

24.4. Interactions Mediated by Peptide Transporters
24.5. Interactions Mediated by Monocarboxylate Transporters
24.6. Interactions Mediated by the Nucleoside Transporters
24.7. Interactions Mediated by the Folate Uptake Transporter
24.8. Conclusions
References
24.1. INTRODUCTION
In patients, drug-drug interactions can result in unexpected life-threatening and even
lethal toxicities. Up to 10% of all hospital admissions in general hospitals are caused
by improper use of drugs and combinations of drugs, resulting in potentially severe
drug-drug interactions. 1 , 2 Adverse drug reactions can be especially severe when these
interactions involve cytotoxic anticancer agents. 3 , 4 Anticancer drugs are dosed close to
the maximum dose tolerated, and factors affecting the pharmacokinetics may therefore
greatly increase the likelihood of development of life-threatening toxicities. Thus far,
drug-drug interactions have been thought to result from inhibition of drug metabolism,
displacement out of the protein binding, or pharmaceutical interactions. However,
interference at the level of the ATP-binding cassette (ABC) and other transporters is
increasingly being identified as the mechanism behind clinically important drug-drug
interactions. These factors are the subject of this chapter.
24.2. INTERACTIONS MEDIATED BY ABC DRUG TRANSPORTERS
24.2.1. ABCB1 (MDR1, P-Glycoprotein)
Impact of Polymorphism on Function Currently, at least 105 variants of the ABCB1
gene have been identified, with significant differences in their frequencies among dif-
ferent ethnic groups. The majority of these single-nucleotide polymorphisms (SNPs)
involve intronic or noncoding regions, thus do not affect the P-glycoprotein (Pgp)
amino acid sequence, whereas several variants in the ABCB1 coding regions result
in amino acid change and potentially affect Pgp expression and activity. Hoffmeyer
et al. reported an association between an SNP in exon 26 (C3435T) of ABCB1, re-
duction in duodenal Pgp levels, and higher peak plasma concentrations of the Pgp
substrate digoxin in healthy volunteers. 5 Confirming and contradicting studies have
subsequently been published about the influence of SNPs in ABCB1 on the disposi-
tion of digoxin and on other Pgp substrate drugs (such as fexofenadine, tacrolimus,
irinotecan, SN-38, paclitaxel, and cyclosporin A) and on Pgp expression and activity
(for reviews, see refs. 6 to 13).