CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 795

Indeed, the extraneural uptake-2 system was first discovered in myocardiocytes of
the heart in rats, and high expression of Oct3 has been reported in heart of rodents
and humans. 687 In addition, the placenta was identified as a novel site of the ex-
traneuronal uptake-2 system: in pregnant females of an Oct3 heterozygous cross, a
threefold-reduced MPP + accumulation after intravenous administration was found in
Oct3 ( − / − ) compared with wild-type fetuses. 683 No difference in MPP + uptake was
found in other Oct3-expressing organs, probably due to the functional redundancy
within the different OCTs and other transporters.

Drug-Drug Interactions A number of drug-drug interactions probably mediated
by OCTs have been described. A drug-drug interaction has been observed between
the H2-receptor inhibitor cimetidine and the antiarrythmic procainamide. Treatment
with cimetidine is reported to increase the AUC significantly and to reduce the renal
clearance of coadministered procainamide. 688 Similarly, coadministration of cime-
tidine with the biguanide metformin has been shown to increase the plasma levels
and to reduce the renal excretion of metformin, thus leading to clinically relevant
consequences. 689 Recently, a clinically relevant interaction was reported between the
antiarrythmic drug pilsicainide and the H1-receptor antagonist cetirizine in a Japanese
patient with moderate renal insufficiency. In a subsequent study using healthy vol-
unteers, when these two drugs were coadministered, they mutually inhibited renal
clearance and decreased their elimination constant. Moreover, as in vitro studies both
cetirizine and pilsicainide were able to inhibit the transport of substrates mediated by
MDR1 and OCT2, and pilsicainide was reported to be excreted into urine probably
via both MDR1 and OCT2, it has been suggested that this drug interaction may be
mediated by both MDR1 and OCT2. 690 In a previous study in healthy volunteers
coadministration of pilsicainide and cimetidine resulted in an increased AUC of pilsi-
cainide by on average 33%, a prolonged elimination half-life, and a reduced apparent
renal clearance of pilsicainide. 691

24.3.4. Organic Cation/Carnitine Transporters

Impact of Polymorphism on Function Recently, single-nucleotide polymorphisms
(SNPs) of OCTN1 have been identified in the Japanese population. Two SNPs (G462E
and T306I) have been functionally characterized: The single amino acid mutation
T306I does not seem to affect TEA transport activity, whereas the G462E mutation
altered OCTN1 transport activity, presumably affecting the physiological function
of OCNT1 and the pharmacokinetics of its substrate drugs. 692 Several mutations of
OCTN2 causing loss of uptake activity and certain silent polymorphisms of OCTN2
have been reported in ethnically diverse subjects, in patients affected by primary
carnitine deficiency, and in some of their relatives; their impact on the pharmaco-
logical profile of substrate drugs needs to be investigated further. 693 - 699 However, it
is likely that mutations causing loss of carnitine transport ability may result in re-
duced transport of the fourth-generation

-lactam antibiotics (such as cefepime and
cefoselis) that are reported to interact with OCTN2. Therefore, it has been proposed
that patients with systemic carnitine deficiency may have reduced distribution and