Sapropterin
Names | |
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Trade names | Kuvan, Biopten, other |
Other names | Tetrahydrobiopterin, Sapropterin hydrochloride (JAN JP), Sapropterin dihydrochloride (USAN US) |
IUPAC name
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Clinical data | |
Main uses | Phenylketonuria, tetrahydrobiopterin deficiency[1][2] |
Side effects | Headache, runny nose, anaphylaxis, stomach inflammation, hyperactivity[1][2] |
Pregnancy category | |
Routes of use | By mouth |
Duration of action | 24 hours[1] |
Typical dose | 5-20 mg/kg per day[4] |
External links | |
AHFS/Drugs.com | Monograph |
MedlinePlus | a608020 |
Legal | |
License data |
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Legal status | |
Pharmacokinetics | |
Elimination half-life | 4 hours (healthy adults) 6–7 hours (PKU patients) |
Chemical and physical data | |
Formula | C9H15N5O3 |
Molar mass | 241.251 g·mol−1 |
3D model (JSmol) | |
SMILES
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InChI
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Sapropterin, also known as tetrahydrobiopterin (BH4, THB), is a medication used to treat phenylketonuria or tetrahydrobiopterin deficiency.[1][2] It is used together with dietary changes.[1] Levels of phenylalanine in the blood are measured during the first month to determine if it is effective.[1] It is taken by mouth.[1]
Common side effects include headache and runny nose.[2] Other side effects may include anaphylaxis, stomach inflammation, and hyperactivity.[1] Use may be considered in pregnancy if diet alone does not control phenylalanine levels.[5] It is a cofactor which improves the activity of phenylalanine hydroxylase (PAH), which breaks down phenylalanine.[1]
Sapropterin was approved for medical use in the United States in 2007,[1] Europe in 2008,[2] and Canada in 2010.[6] In Canada it costs about 48,000 to 168,000 CAD a year for a 68 kg person in 2017.[4] In the United States this amount costs 38,000 to 152,000 USD per year while in the United Kingdom it is about £25,000 to £100,000 as of 2021.[7][8] It is sold under the brand names Kuvan and Biopten.[9]
Medical use
Tetrahydrobiopterin deficiency
Sapropterin is used in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency.[10] Use is not recommended by the Scottish Medicines Consortiums as they view the cost benefit as unclear as of 2021.[1]
Phenylketonuria
Sapropterin is used in phenylketonuria (PKU), along with dietary measures.[11] However, many people with PKU have little or no benefit.[12] Benefits are seen in about 20 to 75% of people.[1]
Dosage
The typical dose is 5 to 20 mg/kg per day.[4] A dose of 2 to 5 mg/kg per day may be used in tetrahydrobiopterin deficiency.[8]
Tetrahydrobiopterin is available as a tablet in the form of sapropterin dihydrochloride (BH4*2HCL).[13][14][15]
Side effects
The most common side effects, observed in more than 10% of people, include headache and a running or obstructed nose. Diarrhea and vomiting are also relatively common, seen in at least 1% of people.[16]
Interactions
No interaction studies have been conducted. Because of its mechanism, tetrahydrobiopterin might interact with dihydrofolate reductase inhibitors like methotrexate and trimethoprim, and NO-enhancing drugs like nitroglycerin, molsidomine, minoxidil, and PDE5 inhibitors. Combination of tetrahydrobiopterin with levodopa can lead to increased excitability.[16]
Functions
It is a cofactor of the three aromatic amino acid hydroxylase enzymes,[17] used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide syntheses.[18] Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (Quinonoid dihydrobiopterin).[19]
Tetrahydrobiopterin has multiple roles in human biochemistry. The major one is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, major monoamine neurotransmitters. It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.[17]
Cofactor for tryptophan hydroxylases
Tetrahydrobiopterin is a cofactor for tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP).
Cofactor for phenylalanine hydroxylase
Phenylalanine hydroxylase (PAH) catalyses the conversion of L-phenylalanine (PHE) to L-tyrosine (TYR). Therefore, a deficiency in tetrahydrobiopterin can cause a toxic buildup of L-phenylalanine, which manifests as the severe neurological issues seen in phenylketonuria.
Cofactor for tyrosine hydroxylase
Tyrosine hydroxylase (TH) catalyses the conversion of L-tyrosine to L-DOPA (DOPA), which is the precursor for dopamine. Dopamine is a vital neurotransmitter, and is the precursor of norepinephrine and epinephrine. Thus, a deficiency of BH4 can lead to systemic deficiencies of dopamine, norepinephrine, and epinephrine. In fact, one of the primary conditions that can result from GTPCH-related BH4 deficiency is dopamine-responsive dystonia;[20] currently, this condition is typically treated with carbidopa/levodopa, which directly restores dopamine levels within the brain.
Cofactor for nitric oxide synthase
Nitric oxide synthase (NOS) catalyses the conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO). Among other things, nitric oxide is involved in vasodilation, which improves systematic blood flow. The role of BH4 in this enzymatic process is so critical that some research points to a deficiency of BH4 – and thus, of nitric oxide – as being a core cause of the neurovascular dysfunction that is the hallmark of circulation-related diseases such as diabetes.[21]
Cofactor for ether lipid oxidase
Ether lipid oxidase (alkylglycerol monooxygenase, AGMO) catalyses the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol.
Biosynthesis and recycling
Tetrahydrobiopterin is biosynthesized from guanosine triphosphate (GTP) by three chemical reactions mediated by the enzymes GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR).[22]
BH4 can be oxidized by one or two electron reactions, to generate BH4 or BH3 radical and BH2, respectively. Research shows that ascorbic acid (also known as ascorbate or vitamin C) can reduce BH3 radical into BH4,[23] preventing the BH3 radical from reacting with other free radicals (superoxide and peroxynitrite specifically). Without this recycling process, uncoupling of the endothelial nitric oxide synthase (eNOS) enzyme and reduced bioavailability of the vasodilator nitric oxide occur, creating a form of endothelial dysfunction.[24] Ascorbic acid is oxidized to dehydroascorbic acid during this process, although it can be recycled back to ascorbic acid.
Folic acid and its metabolites seem to be particularly important in the recycling of BH4 and NOS coupling.[25]
History
Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase (PAH).[26]
Society and culture
BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020.[27]
Research
Autism
In 1997, a small pilot study was published on the efficacy of tetrahydrobiopterin (BH4) on relieving the symptoms of autism, which concluded that it "might be useful for a subgroup of children with autism" and that double-blind trials are needed, as are trials which measure outcomes over a longer period of time.[28] In 2010, Frye et al. published a paper which concluded that it was safe, and also noted that "several clinical trials have suggested that treatment with BH4 improves ASD symptomatology in some individuals."[29]
Cardiovascular disease
Since nitric oxide production is important in regulation of blood pressure and blood flow, thereby playing a significant role in cardiovascular diseases, tetrahydrobiopterin is a potential therapeutic target. In the endothelial cell lining of blood vessels, endothelial nitric oxide synthase is dependent on tetrahydrobiopterin availability.[30]
References
- 1 2 3 4 5 6 7 8 9 10 11 12 "Sapropterin Monograph for Professionals". Drugs.com. Archived from the original on 29 August 2021. Retrieved 10 October 2021.
- 1 2 3 4 5 "Kuvan". Archived from the original on 14 August 2020. Retrieved 10 October 2021.
- 1 2 "Sapropterin (Kuvan) Use During Pregnancy". Drugs.com. 17 May 2019. Archived from the original on 29 October 2020. Retrieved 4 March 2020.
- 1 2 3 "Sapropterin dihydrochloride (Kuvan)" (PDF). CADTH. September 2017. Archived (PDF) from the original on 11 February 2020. Retrieved 10 October 2021.
- ↑ "Sapropterin (Kuvan) Use During Pregnancy". Drugs.com. Archived from the original on 29 October 2020. Retrieved 10 October 2021.
- ↑ Patient Group Input Submissions: sapropterin dihydrochloride (Kuvan) for Phenylketonuria (PKU). Canadian Agency for Drugs and Technologies in Health. 2017. Archived from the original on 12 October 2021. Retrieved 10 October 2021.
- ↑ "Sapropterin Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 29 August 2021. Retrieved 10 October 2021.
- 1 2 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1139. ISBN 978-0-85711-369-6.
- ↑ "Australian Public Assessment Report for Sapropterin dihydrochloride" (PDF). Archived (PDF) from the original on 12 October 2021. Retrieved 10 October 2021.
- ↑ "Tetrahydrobiopterin Deficiency". National Organization for Rare Disorders (NORD). Archived from the original on 21 March 2021. Retrieved 9 October 2017.
- ↑ "What are common treatments for phenylketonuria (PKU)?". NICHD. 23 August 2013. Archived from the original on 5 October 2016. Retrieved 12 September 2016.
- ↑ Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, et al. (June 2014). "Phenylketonuria Scientific Review Conference: state of the science and future research needs". Molecular Genetics and Metabolism. 112 (2): 87–122. doi:10.1016/j.ymgme.2014.02.013. PMID 24667081. Archived from the original on 24 November 2018. Retrieved 10 October 2021.
- ↑ Schaub J, Däumling S, Curtius HC, Niederwieser A, Bartholomé K, Viscontini M, et al. (August 1978). "Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis". Archives of Disease in Childhood. 53 (8): 674–6. doi:10.1136/adc.53.8.674. PMC 1545051. PMID 708106.
- ↑ "Kuvan- sapropterin dihydrochloride tablet Kuvan- sapropterin dihydrochloride powder, for solution Kuvan- sapropterin dihydrochloride powder, for solution". DailyMed. 13 December 2019. Archived from the original on 24 March 2021. Retrieved 4 March 2020.
- ↑ "Kuvan EPAR". European Medicines Agency (EMA). 4 March 2020. Archived from the original on 14 August 2020. Retrieved 4 March 2020.
- 1 2 Haberfeld, H, ed. (1 March 2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Kuvan 100 mg-Tabletten.
{{cite book}}
: CS1 maint: unrecognized language (link) - 1 2 Kappock TJ, Caradonna JP (November 1996). "Pterin-Dependent Amino Acid Hydroxylases". Chemical Reviews. 96 (7): 2659–2756. doi:10.1021/CR9402034. PMID 11848840.
- ↑ Całka J (2006). "The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons". Folia Histochemica et Cytobiologica. 44 (1): 3–12. PMID 16584085. Archived from the original on 29 August 2021. Retrieved 10 October 2021.
- ↑ Bhagavan, N. V. (2015). Essentials of Medical Biochemistry With Clinical Cases, 2nd Edition. USA: Elsevier. p. 256. ISBN 978-0-12-416687-5.
- ↑ "Genetics Home Reference: GCH1". National Institutes of Health. Archived from the original on 27 June 2020. Retrieved 10 October 2021.
- ↑ Wu G, Meininger CJ (2009). "Nitric oxide and vascular insulin resistance". BioFactors. 35 (1): 21–7. doi:10.1002/biof.3. PMID 19319842. S2CID 29828656.
- ↑ Thöny B, Auerbach G, Blau N (April 2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions". The Biochemical Journal. 347 Pt 1: 1–16. doi:10.1042/0264-6021:3470001. PMC 1220924. PMID 10727395.
- ↑ Kuzkaya N, Weissmann N, Harrison DG, Dikalov S (June 2003). "Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase". The Journal of Biological Chemistry. 278 (25): 22546–54. doi:10.1074/jbc.M302227200. PMID 12692136.
- ↑ Muller-Delp JM (November 2009). "Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability". Cardiovascular Research. 84 (2): 178–9. doi:10.1093/cvr/cvp307. PMID 19744948.
- ↑ Gori T, Burstein JM, Ahmed S, Miner SE, Al-Hesayen A, Kelly S, Parker JD (September 2001). "Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study". Circulation. 104 (10): 1119–23. doi:10.1161/hc3501.095358. PMID 11535566.
- ↑ Kaufman S (February 1958). "A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine". The Journal of Biological Chemistry. 230 (2): 931–9. doi:10.1016/S0021-9258(18)70516-4. PMID 13525410.
{{cite journal}}
: CS1 maint: url-status (link) - ↑ "BioMarin Announces Kuvan (sapropterin dihydrochloride) Patent Challenge Settlement". BioMarin Pharmaceutical Inc. 13 April 2017. Archived from the original on 28 November 2020. Retrieved 9 October 2017 – via PR Newswire.
- ↑ Fernell E, Watanabe Y, Adolfsson I, Tani Y, Bergström M, Hartvig P, et al. (May 1997). "Possible effects of tetrahydrobiopterin treatment in six children with autism--clinical and positron emission tomography data: a pilot study". Developmental Medicine and Child Neurology. 39 (5): 313–8. doi:10.1111/j.1469-8749.1997.tb07437.x. PMID 9236697. S2CID 12761124.
- ↑ Frye RE, Huffman LC, Elliott GR (July 2010). "Tetrahydrobiopterin as a novel therapeutic intervention for autism". Neurotherapeutics. 7 (3): 241–9. doi:10.1016/j.nurt.2010.05.004. PMC 2908599. PMID 20643376.
- ↑ Channon KM (November 2004). "Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease". Trends in Cardiovascular Medicine. 14 (8): 323–7. doi:10.1016/j.tcm.2004.10.003. PMID 15596110.
External links
Identifiers: |
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- "Sapropterin". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 23 April 2021. Retrieved 10 October 2021.
- "Clinical Review Report: Sapropterin dihydrochloride (Kuvan)". CADTH Common Drug Reviews. Ottawa, Canada: Canadian Agency for Drugs and Technologies in Health (CADTH). September 2017. Bookshelf ID: NBK533813. Archived from the original on 8 December 2019. Retrieved 10 October 2021.
- Blau N (June 2016). "Genetics of Phenylketonuria: Then and Now". Human Mutation. 37 (6): 508–15. doi:10.1002/humu.22980. PMID 26919687.
- Dubois EA, Cohen AF (June 2010). "Sapropterin". British Journal of Clinical Pharmacology. 69 (6): 576–7. doi:10.1111/j.1365-2125.2010.03643.x. PMC 2883749. PMID 20565448.
- Muntau AC, Adams DJ, Bélanger-Quintana A, Bushueva TV, Cerone R, Chien YH, et al. (May 2019). "International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria". Molecular Genetics and Metabolism. 127 (1): 1–11. doi:10.1016/j.ymgme.2019.04.004. PMID 31103398.
- Qu J, Yang T, Wang E, Li M, Chen C, Ma L, et al. (May 2019). "Efficacy and safety of sapropterin dihydrochloride in patients with phenylketonuria: A meta-analysis of randomized controlled trials". British Journal of Clinical Pharmacology. 85 (5): 893–899. doi:10.1111/bcp.13886. PMC 6475685. PMID 30720885.
- van Wegberg AM, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, et al. (October 2017). "The complete European guidelines on phenylketonuria: diagnosis and treatment". Orphanet Journal of Rare Diseases. 12 (1): 162. doi:10.1186/s13023-017-0685-2. PMC 5639803. PMID 29025426.