CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 803

Clinically relevant drug-drug interactions mediated by PEPT at the intestinal ab-
sorption level may be postulated between certain sulfonylureas and peptidelike coad-
ministered drugs. As several sulfonylureas, such as nateglinide, glibenclamide, and
tolbutamide, appear to be good inhibitors of PEPT1 activity, oral coadministration of
glibenclamide or nateglinide and

-lactam antibiotics to diabetic patients may lead to
a reduction in the oral bioavailability of the -lactam compounds, thereby affecting

their plasma levels and possibly also their therapeutic efficacy. 758 , 759
On the other hand, taken in consideration the postulated involvement of PEPT1
in intestinal inflammation via transport of the neutrophil chemotactic factor formyl-
Met-Leu-Phe, the activity of PEPT2 at the renal and brain level and the affinity of
both peptide transporters for -ALA, long-term administration of PEPT inhibitors,

such as glibenclamide or nateglinide, might affect states of intestinal inflammation,
porphyrin metabolism, and brain tissue drug delivery. It is of interest to explore
these concepts further preclinically and eventually, test the clinical feasibility in
patients.

24.5. INTERACTIONS MEDIATED BY MONOCARBOXYLATE
TRANSPORTERS

Impact of Polymorphism on Function Mutations of monocarboxylate transporters
(MCTs) have been reported to cause lactate transport deficiency with important patho-
physiological effects. Some decades ago an otherwise healthy patient who developed
severe chest pain and elevated serum creatine kinase levels after heavy exercise has
been described. He was reported to have a defective red cell lactate efflux and a delayed
reduction in muscle lactate after exercise. 808 In a subsequent study, genetic analysis
of this patient and other subjects with reported defective lactate transport led to the
identification of missense mutations of MCT1 gene with altered protein function. 809
Recently, mutations of MCT8 (a MCT that has been shown to participate in thyroid
hormone transport and metabolism) have been identified, and several of them have
been associated with the Allan-Herndon-Dudley syndrome (AHDS), an X-linked
condition characterized by severe mental retardation, neurological dysfunction, and
elevated serum triiodothyronine (T3) levels. 810 - 812

Main Substrates Classes (Clinically Applied) MCT1 substrates consist of a broad
range of short-chain monocarboxylates, especially those substituted in the C2
and C3 positions such as lactate, pyruvate, acetoacetate,

-hydroxybutyrate, some

branched-chain keto acids (e.g., -ketoisocaproate), and acetate, proprionate, and

butyrate. 813 , 814 MCT1, as well as other MCTs, is also able to transport some exoge-
nous or pharmacologically active compounds, usually consisting of monovalent weak
organic acids with the carboxyl bound to a lateral small hydrophobic or hydrophilic
group. Putative clinically relevant MCT1 substrates include salicylic acid, benzoic
acid, nicotinic acid, foscarnet, and R - and S -mandelic acid. 815 - 817 MCTs in general,
and MCT1 in particular, have been implicated in the transport of some -lactam antibi-

otics (e.g., phenethicillin, propicillin, carindacillin) 818 , 819 and HMG-CoA reductase