CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 796

altered pharmacological profile (in particular, increased renal clearance and there-
fore decreased systemic half-life) of -lactam antibiotics and other OCTN2 substrate

drugs. 700

Main Substrates Classes (Clinically Applied) and Inhibitors (Competitive and
Noncompetitive) Carnitine and carnitine esters (acetyl- and propionylcarnitine), to-
gether with other important organic cations, are the main physiological substrates
of OCTN1 and OCTN2. OCTN1 and OCTN2 substrates include TEA and the Ca 2 +
antagonists verapamil and quinidine. OCTN2 has been reported to transport betaine,
choline, lysine, and methionine. 701 In in vitro models of several clinically applied

drugs, such as the -lactam antibiotics cephaloridine, cefepime, cefoselis, and ce-

fluprenam, were reported to inhibit OCTN2-mediated carnitine transport in a com-
petitive manner, suggesting themselves being substrates of OCTN2. 700 Analogously,
widely used compounds such as quinidine, procainamide, desipramine, cimetidine,
clonidine, emetine, and the hormones aldosterone and corticosterone compete with
carnitine and/or acetylcarnitine for OCTN2 transport. 698 , 702 , 703 OCTN1 is inhibited
by structurally diverse compounds, including cephaloridine, quinine, cimetidine, pro-
cainamide, and pyrilamine. 703
Valproic acid seems to interfere with the regulation or synthesis of carnitine trans-
porters, and it or its metabolites are reported to be responsible for inhibition of
L-carnitine transport in cell cultures. 700 , 702 , 704 Emetine (an antiamebic and emetic
compound) and pivalic acid (a substance contained in several antibiotics used in the
treatment of respiratory and urinary tract infections) have been reported to inhibit
OCTN2 activity. In humans, long-term treatment with emetine and pivalic acid, as
well as therapy with valproic acid and betaine, may lead to a secondary or acquired
systemic carnitine deficiency. 701 , 704 - 709

Pharmacological and Toxicological Function, and Interactions Organic cation/
carnitine transporters are physiologically important in mediating the transport of
carnitine, carnitine ester derivatives, and several organic cations. OCTN substrates
include also a number of clinically relevant drugs. These findings, together with
the wide tissue distribution of OCTNs and the observation that OCTN activity
may be inhibited by a variety of xenobiotics, suggest a significant pharmacologi-
cal and toxicological role for OCTNs. At the renal level OCTN2 mediates the re-
absorption of substrate drugs, thus affecting their disposition and clearance. Conse-
quently, by increasing the systemic half-life of substrate drugs, OCTN2 may enhance
their therapeutic efficacy and modulate their toxicological properties. For instance,
one of the reported mechanisms of nephrotoxicity caused by the -lactam antibi-

otic cephaloridine is competition with carnitine transport at the level of OCTN2
in renal tubular cells and mitochondria, possibly leading to renal mitochondrial
damage. 710 , 711
OCTN1 and OCTN2 have also been proposed to affect the intestinal absorption
and pharmacokinetic behavior of a number of drugs. In rats, oral administration of
sulpiride, a dopamine D 2 receptor antagonist, with OCTN1 and OCTN2 substrates
and/or inhibitors decreased the plasma sulpiride concentration. 712 , 713 Moreover,