Phenylketonuria administration

A Fig. 6.1.7a- HPLC of pterins using a column-switching system a standard mixture b control urine c urine guanosine triphosphate cyclohydrolase I (GTPCH) deficiency d urine 6-pyru-voyl-tetrahydropterin synthase (PTPS) deficiency e urine pterin-4a-carbinolamine dehydratase (PCD) deficiency f urine dihydropteridine reductase (DHPR) deficiency g urine phenylketonuria 4-8 h after tetrahydrobiopterin (BH4) administration h-k see next page... 

The original formulation, a buffered powder, has been replaced by chewable and dispersible buffered tablets with greater bioavailability (30-40%) a new enteric-coated formulation further improves patient convenience and tolerability. Since the chewable tablets contain both phenylalanine (36.5 mg) and sodium (1380 mg), caution should be exercised in patients with phenylketonuria and those taking sodium-restricted diets. Didanosine should be taken on an empty stomach and, because of the buffered formulation, should be administered at least 2 hours after administration of drugs requiring acidity for optimal absorption (eg, ketoconazole, itraconazole, dapsone). 

M10. Meister, A., Udenfriend, S., and Bessman, S. P., Diminished phenylketonuria in phenylpyruvic oligophrenia after administration of L-glutamine, L-glutamate, or L-asparagine. J. Clin. Invest. 36, 619-626 (1956). 

Other data show that under disease state, transport systems may be less available to transport compounds into the brain. It was demonstrated that the transport of phenylalanine by LAT into the brain of patients with phenylketonuria was blocked (120). In addition, EEG analysis revealed that brain activity was acutely disturbed when phenylalanine was given orally without other LNAAs. Following administration with LNAAs, phenylalanine influx was completely blocked and no influence on EEG could be observed. 

When diketopiperazines are administered to humans intravenously, they are not assimilated and are excreted unchanged in the urine. However, oral administration of compound 148 results in the breakdown of the compound, presumably in the digestive tract, and it therefore cannot be detected in the urine. " In contrast, people with phenylketonuria, who are fed on a low phenylalanine diet, excrete large amounts of the diketopiperazine 149. Although this compound is found in small amounts in the urine of normal hiunans, the excessive excretion of this diketopiperazine has been shown not to be due to a metabolic defect. Instead the compound originates in the diet itself and is not metabolized in the human digestive tract. ... 

Artificial cells have been used in hereditary enzyme defects, including our earliest use of a replacement for catalase in acatalasemic mice. This also has been studied for asparagine removal in the treatment of leukemia in animals."" We used phenylalanine ammonia lyase artificial cells in phenylketonuria rats." Later, we found an extensive enterore-circulation of amino acids in the intestine." This allows enzyme artificial cells to be used orally to selectively remove specific amino acids from the body, as in phenylketonuria." We also studied the oral administration of artificial cells containing xanthine oxidase." " This resulted in a decrease in systemic hypoxanthine in a pediatric patient with hypoxanthinuria (Lesch-Nyhan disease). 

MacDoneild A, Rylance G, Davies P, Asplin D, HaU SK, Booth IW. Administration of protein substitute and quality of control in phenylketonuria a randomized study. J Inherit Metab Dis. 2003 26(4) 319-26. 

Metabolic Alterations, Many of the biochemical anomalies of phenylketonuria can be explained by the inhibition or absence of phenylalanine hydroxylase. The evidence in favor of this mode of pathogenesis is both direct and indirect. The indirect evidence is based on the metabolic experiments of Jervis, who administered a variety of amino acids to phenylketonuric patients and demonstrated that only phenylalanine increases the urinary excretion of phenylalanine and all its derivatives phenylpyruvic, phenyllactic, and phenylacetic acids. These experiments suggest that the block in the phenylalanine-tyrosine pathway is located beyond phenylalanine. Since tyrosine administration to phenylketonuric patients did not produce such effects, the block was assumed to be located between phenylalanine and tyrosine. This was confirmed by isotope experiments. When labeled phenylalanine is administered to normal patients, radioactivity is soon recovered in tyrosine and in proteins. In phenylketonuric patients, most of the radioactivity is recovered in the urine, and practically none is found in the protein. The administration of phenylpyruvic acid and phenylacetic acid demonstrated that in the phenylketonuric patient there is no block in the conversion of these compounds into phenylalanine. However, the most conclusive evidence was obtained when Jervis studied autopsy specimens from normal and phenylketonuric individuals and demonstrated that phenylalanine hydroxylase activity is practically nonexistent in phenylketonuric patients [76]. 

An early form of therapy involves eliminating the substrate either by excluding the substrate from the diet, as in phenylketonuria, or by administering drugs—such as penicillamine in Wilson s disease or allopurinol in gout. Orotic aciduria can be corrected by the administration of uridine, which provides the substrate for the biosynthesis of the nucleosides used in RNA and DNA synthesis and is also a substrate for the biosynthesis of inhibitors of the carbamyl aspartate synthetase, the first enzyme in the formation of orotic acid. By this feedback inhibition, the levels of orotic acid in the urine are reduced by the administration of uridine. 

---