Methyldopa, amino acid transporters

Pharmacokinetic characteristics of methyldopa are listed in Table 11-2. Methyldopa enters the brain via an aromatic amino acid transporter. The usual oral dose of methyldopa produces its maximal antihypertensive effect in 4-6 hours, and the effect can persist for up to 24 hours. Because the effect depends on accumulation and storage of a metabolite (a-methylnorepinephrine) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation. 

L-a-methyldopa a substrate for the amino acid transporter. In Caco-2 cells, the active transport of this dmg by the amino acid transporter was seven times higher than transport by passive diffusion. Its absorption may be further increased by upregulating the amino acid transporter, as has been observed in the 20-70% stimulation of carrier-mediated amino acid transport by treatment of 0.2 mg/kg growth hormone. 

ABSORPTION, METABOLISM, AND EXCRETION When administered oraUy, methyldopa is absorbed by an active amino acid transporter. Peak plasma concentrations occur after 2-3 hours. The drug is eliminated with a of 2 hours (prolonged to 4-6 hours in patients with renal failure). Methyldopa transport into the CNS apparently is an active process. Methyldopa is excreted in the urine primarily as the sulfate conjugate (50-70%) and as the parent drug (25%). The remainder is excreted as other metabolites, including methyldopamine, methylnorepinephrine, and O-methylated products of these catecholamines. 

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored however, unlike the endogenous mediator, it has a higher affinity for a2- than for ai-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. 

Drags which have structures similar to that of endogenous nutrients may be taken up by a specialized transport system (carrier-mediated transport, receptor-mediated transcytosis) existing in the brain endothelium for nutrients. For example, drags having a molecular structure similar to a large neutral amino acid may cross the BBB via the neutral amino acid carrier such drags include melphalan (phenylalanine mustard), L-dopa, a-methyldopa, and p-chlorophenylalanine. 

As discussed above, certain nutrients are taken up into the brain by carrier-mediated systems. If a dmg possesses a molecular structure similar to that of a nutrient which is a substrate for carrier-mediated transport (Table 13.1), the pseudo-nutrient dmg may be transported across the BBB by the appropriate carrier-mediated system. For example, the dmg L-dopa crosses the BBB via the neutral amino acid carrier system. Other neutral amino acid dmgs that are transported through the BBB on this transport system are a-methyldopa, a-methylparatyrosine, and phenylalanine mustard. 

Orally administered amines do not cross the blood-brainbarrier, but neutral amino acids such as a-methyldopa are transported into the brain by a specific carrier system. a-Meth-yldopa is subsequently concentrated in neuronal cells, where it becomes a substrate in the catecholamine biosynthesis and is transformed into a-methylnoradrenaline (180). 

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