The article, Pharmacokinetics of sapropterin in patients with phenylketonuria was about a treatment method found to help treat those with phenylketonuria. Phenylketonuria is an inborn error in amino acids metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase (1). A phenylalanine hydroxylase deficiency leads to high blood phenylalanine levels. Pathogenesis is the process of converting phenylalanine to tyrosine. Phenylketonuria collects in all body fluids, because it cannot be converted into tyrosine. A large amount of phenylalanine is converted into tyrosine where as a small portion is integrated into proteins. Phenylketonuria has a pathway that is blocked which causes blood levels of phenylalanine to be extremely higher than levels of a normal healthy human (2). Phenylalanine is an essential amino acid, meaning the body does not make it and it is essential that one must consume it through nutrition.
Phenylalanine is supposed to be broken down by phenylalanine hydroxylase. During hydroxylation, phenylalanine needs certain cofactors and enzymes to allow for the production of tyrosine to occur (3). For the translation to occur the process must involve phenylalanine hydroxylase, cofactor tetrahydrobiopterin (BH4), and other enzymes like dihydropteridine reductase and 4α-carbinolamine dehydratase to assist in the restoration of tetrahydrobiopterin (4). When phenylketonuria is in question it’s the deficiency of the enzyme phenylalanine hydroxylase that is not present, meaning phenylalanine cannot be further broken down which leads to the increase levels of phenylalanine in blood.
Usually those with phenylketonuria manage their disease with a protein-restricted diet. The difficulty issue with diets is there is often a failure to comply with the routine of the diet. Supplementation of BH4 has been proven to reduce plasma phenylalanine levels for phenylketonuria patients. Neutral amino acid supplementation works off in a reverse method of L-Phenylalanine to induce the inhibition of the amino acids to cross the blood-brain barrier (5). The blood brain barrier allows a competitive inhibition of the uptake of phenylalanine by the neutral amino acids. One supplement that is on the market that many Phenylketonuria patients have chosen to use is Kuvan, which is saproterin dihydrochoride tablets. Sapropterin dihydrochloride is known and one of the first medical therapies along with diet for phenylketonuria (6). In many trials this product has been tested and it has been proven that it helps control blood phenylalanine levels in Phenylketonuria patients (7). Tetrahydrobiopterin (BH4) is that helps in lowering the levels.
Sapropterin dihydrochloride, also referred to as sapropterin is an artificial invention of 6R-tetrahydrobiopterin (6R-BH4), which had been proven to be effective in decreasing the blood phenylalanine levels in patients with phenylketonuria. The purpose of the study in Pharmacokinetics of saproterin in patients with phenylketonuria was to identify the characteristics that influence variability of sapropterin.
The study lasted for twelve weeks with fixed amount of doses given to the patients. Patients with phenylketonuria were allowed to participate in the study if there were at least eight years of age and if they had taken the recommended doses in another study that was prior to this twelve week study. There were a total of 78 patients that were involved in this study. The patients received oral once a day doses of sapropterin (Kuvan) in the amounts of 5, 10 or 20 mg/kg. The results showed that the amount of saproterin needed to lower the levels of phenylalanine was based on the patient’s bodyweight, but for all patients the supplement worked and lowered the levels (8).
The topic of phenylketonuria has become an interest of my over the past semester, because I have been doing research on it for a paper. I began to feel sympathetic for those who have this condition, because it can take over one’s life if not treated at a young age and treatment continue throughout their life. If makes one think how hard their life really is, when you look at someone who just may have it a little harder than you.
References:
1. Ding, Z, P Georgiev, and B Thony. “Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. (Original Article). “ Gene Therapy 13.7 (2006): 587. Academic OneFile. Web.31 Jan. 2011.
2. Tymoczko, John, Jeremy Berg, and Lubert Stryer. Biochemistry: A Short Course. W H
Freeman &Co, 2010. Print.
3. Harding CO. Progress towards cell-directed therapy for phenylketonuria. Clin Genet
2008: 74: 97-104. Blackwell Munksgaard, 2008.
4. Williams, Robin A, Cyril DS Mamotte, and John R Burnett. “ Phenylketonuria: An
Inborn Error of Phenylalanine Metabolism. Clin Biochem Rev. 2008 Februrary;26(1):31-41.
5. Pey, Angel L., et al. “Identification of pharmacological chaperones as potential
therapeutic agents to treat phenylketonuria.” Journal of Clinical Investigation
118.8 (2008):2858+. General OneFile. Web.31 Jan.2011
6. Thompson, Cheryl A. “First drug approved for treatment of phenylketonuria.” American
Journal of Health-System Pharmacy 65.2 (2008): 100. Academic One File.Web.31 Jan. 2011.
7. Rollins, Judy A. “First specific drug therapy approved for the treatment of PKU.”
Pediatric Nursing 34.2 (2008): 182. General OneFile. Web.31 Jan 2011.
8. Feillet, Francois, et al. “Pharmacokinetics of sapropterin in patients with
phenylketonuria.” Clinical Pharmacokinetics 47.12 (2008): 817+. Academic OneFile. Web 4 Apr. 2011.
Amber Dowdy
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It says in the study, all the patient’s phenylalanine levels decreased. Is there a possible chance that the drug wouldn’t work for all patients? Are there other methods of supplementation that they could take instead of the Sapropterin?
ReplyDeleteM.Amos
In that particular study all the patient’s did see a decrease in their phenylalanine levels. As far as other studies there have been studies that have shown that the Sapropterin had a 50/50 chance to lower the phenylalanine levels in PKU patients. Diet can help with those patients that don’t show progress with the Sapropterin, as long as those patients don’t fail to comply with their routine of diet. Though supplements have a chance to help with the reduction of the phenylalanine levels, it’s not 100 percent effective in all patients. More studies are still being constructed to further the results on lowering levels by supplementation.
ReplyDelete-Amber D.