CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 797

systemic carnitine deficiency has been associated with long-term treatment with the
antiepileptic valproic acid, the -lactam antibiotic pivampicillin, the emetic and an-

tibiotic emetine, the nucleoside analog zidovudine, and the compound betaine. Al-
though the mechanisms responsible for this drug toxicity have not been characterized
completely, the competitive inhibition of OCTN2-mediated carnitine transport by at
least some of these drugs (valproic acid, emetine) has been reported to cause the drug-
induced carnitine deficiency. These findings suggest that the drug-drug interactions
between carnitine and other OCTN2 substrate drugs mediated by OCTN2 could be
clinically relevant.
Analogously, the inhibitory effect of anticonvulsants on carnitine transport by the
human placental carnitine transporter may cause the fetal anticonvulsant syndrome,
of which some symptoms are similar to the fetal carnitine deficiency phenotype.
Indeed, fetuses and neonates may not be able to synthesize adequate amounts of
carnitine that is essential in fetal metabolic functions and tissue development and
maturation. Recent in vitro experiments performed with vesicles derived from pla-
cental brush border membranes showed that several clinically used anticonvulsants,
in particular valproic acid, phenytoin, and tiagabine, were able to inhibit carnitine
uptake competitively. 714 , 715 Moreover, carnitine supplementation has been described
to reduce the adverse reactions caused by long-term valproic acid treatment. 716 , 717
These findings suggest a possible beneficial role of carnitine supplementation dur-
ing pregnancy in women treated with certain anticonvulsants. However, consider-
ing that carnitine transporters have recently been involved in carnitine transport
across the blood-brain barrier, carnitine administration could competitively inhibit
the uptake of anticonvulsants in the brain. 714 , 718 The drug-drug interactions at the
level of OCTN1 and 2 outlined may have clinical implications; however, it is war-
ranted to investigate this in greater detail. In Table 24.2, examples of clinical drug-
drug interactions probably mediated by organic anion and cation transporters are
reported.

24.4. INTERACTIONS MEDIATED BY PEPTIDE TRANSPORTERS

Impact of Polymorphism on Function To date, no polymorphisms in human
peptide transporter genes have been described. However, based on the relevant
(patho)physiological and pharmacological role of peptide transporters (PEPTs), it
can be predicted that genetic polymorphism in PEPT and peptide/histidine transporter
(PHT) genes may influence the function of the transporters, affect drug disposition,
and contribute to interindividual variability in drug therapy.

Main Substrates Classes (Clinically Applied) There are some differences in sub-
strate specificity and affinity as well as in transport capacity between PEPT1 and
PEPT2. PEPT1 is considered a low-affinity, high-capacity transporter, whereas PEPT2
is a high-affinity, low-capacity system. The physiological substrates of PEPT1 and
PEPT2 include all 400 dipeptides and about 8000 possible tripeptides derived from
the proteogenic L- -amino acids. These transporters are stereoselective, as they