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Transporter-Targeted Prodrugs

Site-specific transport can be achieved by targeting prodrugs to endogenous transporters. Two major endogenous transport mechanisms utilized in CNS drug delivery are receptor-mediated transport (RMT) and carrier-mediated transport [39]. These mechanisms will be discussed in detail in a later section.

The L-amino acid transporter (LAT) is highly expressed on the BBB. It is a type of membrane transport protein that is responsible for importing large neutral amino acids such as L-tyrosine and L-leucine in a Na+-independent manner. Of the various amino acid transporters, LAT-1 is the most abundantly expressed influx transporter on the BBB [40]. This transporter plays a prime role in transporting naturally occurring amino acids as well as amino acid—related products such as L-3,4-dihydroxyphenylalanine (l-DOPA) and gabapentin. Table 4.1 depicts various carriers available for BBB transport by prodrug derivatization.

l-DOPA, a precursor of dopamine, is indicated in Parkinson disease. Carboxylation of dopamine generates l-DOPA, which acts as a pseudonutrient substrate for LAT-1 [41]. Once l-DOPA penetrates into the brain through LAT-1, a decarboxylase enzyme induces decarboxylation of l-DOPA, thus delivering dopamine into the CNS. However, to prevent the premature bioconversion of l-DOPA, patients with Parkinson disease are administered a combination of carbidopa and l-DOPA (Sinemet). Carbidopa acts as a

Table 4.1 Examples of endogenous transporters on brain capillary endothelial cells that can be exploited by carrier-mediated transport systems

Carrier type

Carrier

Representative substrate

LAT1

Neutral amino acid

L-Phenylalanine

GLUT1

Hexose

Glucose

MCT1

Monocarboxylic acid

Lactic acid

CAT1

Cationic amino acid

Arginine

CNT2

Nucleoside

Adenosine

SVCT2

Ascorbic acid

Vitamin C

SMVT

Multivitamin

Biotin

decarboxylase inhibitor and prevents peripheral conversion of l-DOPA to dopamine thus eliminating the risks of side effects. A current research study focused on developing a new hybrid glutathione-methionine peptidomimetic prodrug of l-DOPA to avoid its oxidative degradation in gastric fluid [42].

The broad specificities of various transporters and receptors have opened a wide array of drug modifications by chemical derivatization. Although several endogenous transporter substrate derivatives have been developed and studied extensively, one of the major challenges remains whether the drug is able to maintain its activity in the brain after crossing the BBB. Other issues with this strategy might be complications with the dosing regimens since transporter expression may vary from patient to patient.

 
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