CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 802

of other compounds that become substrates of peptide transporters after modification
by amino acid esterification, thereby improving their pharmacological profile. 796 Fur-
thermore, the peptidic prodrugs of a series of novel aminomethyl tetrahydrofuranyl
(THF)-1 -methylcarbapenems showed higher efficacy and intestinal uptake than that

of the active parent drug molecules. 797
Moreover, both PEPT1 and PEPT2 may, by mediating the renal tubular reabsorp-
tion of substrates, affect the half-life, the clearance, and thereby the pharmacokinetics
of substrate drugs.

-Lactam antibiotics transported by peptide transporters have more
rapid intestinal uptake, increased availability after oral administration, and a longer
half-life than that of antimicrobials that are not PEPT substrates. 789 , 790 Peptide trans-
porters may also affect the tissue distribution of substrates in the body, thus determin-
ing a specific pattern of tissue drug delivery. This characteristic could be exploited
in the treatment of selected diseases. For instance,

-ALA, a precursor of cellular
porphyrin synthesis used widely as a photosensitizer in the photodynamic therapy of
tumors, is a well-known PEPT1 and PEPT2 substrate. This may affect ALA's rapid
intestinal absorption and renal clearance but may also determine its accumulation in
other tissues with PEPT2 expression, such as the brain, mammary gland, and lung,
thus possibly improving under well-selected conditions the response of these organs
to photodynamic therapy. 753 , 798 , 799 In addition, due to the proposed role of PEPT2 in
mediating the influx and efflux of peptides from cerebrospinal fluid, PEPT2 may affect
the disposition of peptidomimetic drugs (e.g., aminocephalosporins and penicillins)
and xenobiotics in the cerebrospinal fluid and the brain. Therefore, the development
of drugs with limited PEPT2 affinity or the design of selective PEPT2 inhibitors
could be a useful strategy to improve brain delivery of drugs aimed to treat brain
disorders. 800 , 801 Finally, PEPTs have been found on the cell membrane of a range
of cancer cells; however, it is currently unknown whether this expression affects the
outcome of anticancer drug therapy.

Drug-Drug Interactions Clinically relevant drug-drug interactions mediated by
peptide transporters have been reported between different -lactam antibiotics and/or

inhibitors of these transporters. Oral coadministration of cefadroxil and cephalexin
has been shown to delay and decrease the time to maximal plasma concentration and
the AUC, respectively, of cefadroxil, presumably due to competitive inhibition by
cephalexin of the intestinal PEPT1-mediated transport of cefadroxil. 802 Analogously,
altered pharmacokinetics of the -lactam ampicillin and amoxycillin were described

after oral administration, together with cyclacillin, to healthy volunteers. These find-
ings, together with evidence obtained previously in rats, suggested competition for
absorption between these penicillins in the human gut at the level of peptide drug
transporters. 803 , 804
Via a different mechanism, nifedipine, a widely used Ca 2 + antagonist, has been ob-
served to increase the bioavailability of orally administered amoxicillin and cefixime
in humans and cephalexin in rats. One of the mechanisms proposed to explain these
drug-drug interactions involves a change in the intestinal surface pH mediated by
nifedipine (due to a decreased concentration of intracellular Ca 2 + ), thereby increas-
ing the driving force for -lactam drug transport mediated by PEPT1. 770 , 791 , 805 - 807