CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 801

Dietary conditions and several pathophysiological states can modulate PEPT ex-
pression: In rats, a brief period of fasting or starvation or administration of a diet
enriched in certain free amino acids and peptides was associated with up-regulation
of PEPT1 expression. 773 - 776 A circadian regulation of intestinal PEPT1 expression
has also been described in rats fed ad libitum and was able to affect the pharmacoki-
netics of the oral antibiotic ceftibuten, a peptidelike drug. However, the diurnal rhythm
of intestinal rat PEPT1 activity was disrupted by fasting. 777 , 778 Diabetes, induced by
treatment of rats with streptozotocin, resulted in an increased expression of PEPT1
in the small intestine. 779 Unusually high intestinal colonic levels of PEPT1 have also
been identified in patients affected by short-bowel syndrome, chronic ulcerative col-
itis, Crohn's disease, or acute cryptosporidiosis, whereas PEPT1 is virtually absent
under normal conditions of the gastrointestinal tract. 780 - 783 A potential role of PEPT1
in inflammatory bowel diseases has recently been suggested, as PEPT1 was reported
to transport formyl-Met-Leu-Phe (fMLP), a neutrophil chemotactic factor produced
by Escherichia coli . 784 , 785 In contrast, endotoxin and lipopolysaccharide are associ-
ated with down-regulation of PEPT1 in animal models. 786 Less is known regarding
modulation of PEPT2 expression: Up-regulation of PEPT2 has been described in
rat remnant kidney after unilateral nephrectomy, which could possibly modulate the
pharmacokinetics of drugs transported by PEPT2 in patients affected by chronic renal
failure. 787

Pharmacological and Toxicological Function The physiological activity, the wide
substrate specificity, and the tissue distribution of peptide transporters suggest that
they could affect the oral bioavailability and the pharmacokinetics of substrate drugs.
In general, compounds that are structurally similar to oligopeptides and are well-
known PEPT1 substrates have good oral bioavailability, whereas their class analogs
not transported by PEPT1 display slower and less complete absorption after oral ad-
ministration. Indeed, in a study comparing several penicillins and cephalosporins, a
significant correlation was found between the in vitro affinity for PEPT1 and their re-
ported oral availability. In particular, aminopenicillins, and aminocephalosporin that
displayed higher affinity and higher in vitro transport rates than other

-lactam an-
tibiotics showed higher absorption rates in vivo. 788 - 790 Moreover, it has been reported
that the expression level of PEPT1 in the rat intestine correlated significantly with
intestinal absorptive transport of cephalexin and cefadroxil. 776 , 791
Based on these findings, a strategy was developed to improve the oral bioavail-
ability of drugs. It consists of coupling an amino acid residue to a drug to obtain a
peptide or a peptidomimetic compound transported by peptide transporters. For exam-
ple, L-dopa-L-Phe, a peptide derivative developed as a prodrug of L-dopa, displayed
an intestinal uptake around 40-fold higher than that of free L-dopa, a drug widely
used in treatment of Parkinson's disease. 792 Analogously, valacyclovir, the L-valyl
ester of acyclovir, a well-known antiviral drug, shows three- to fivefold higher oral
bioavailability than that of free acyclovir, and in in vitro models, valacyclovir, but not
acyclovir, appears to be a PEPT1 substrate. 793 - 796 The examples of L-valine ester of
zidovudine, a compound commonly used in the treatment of HIV infection and the
amino acid esterification of other antiviral nucleosides have led to the development