![]() | |
Clinical data | |
---|---|
Trade names | Kuvan, Biopten |
Other names | Sapropterin hydrochloride (JAN JP), Sapropterin dihydrochloride (USAN US) |
AHFS/Drugs.com | Monograph |
MedlinePlus | a608020 |
License data |
|
Pregnancy category |
|
Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Elimination half-life | 4 hours (healthy adults) 6–7 hours (PKU patients) |
Identifiers | |
| |
CAS Number |
|
PubChem CID | |
IUPHAR/BPS | |
DrugBank |
|
ChemSpider | |
UNII | |
KEGG | |
ChEBI |
|
ChEMBL |
|
PDB ligand | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.164.121 |
Chemical and physical data | |
Formula | C9H15N5O3 |
Molar mass | 241.251 g·mol−1 |
3D model (JSmol) | |
| |
| |
![]() ![]() |
Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN),[5][6] is a cofactor of the three aromatic amino acid hydroxylase enzymes,[7] 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 synthases.[8][9] Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).[10][citation needed]
Medical use
[edit]Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride (BH4*2HCL).[11][3][4] It was approved for use in the United States as a tablet in December 2007[12][13] and as a powder in December 2013.[14][13] It was approved for use in the European Union in December 2008,[4] Canada in April 2010,[2] and Japan in July 2008.[13] It is sold under the brand names Kuvan and Biopten.[4][3][13] The typical cost of treating a patient with Kuvan is US$100,000 per year.[15] BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020.[16]
Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency.[17] Also, BH4*2HCL is FDA approved for use in phenylketonuria (PKU), along with dietary measures.[18] However, most people with PKU have little or no benefit from BH4*2HCL.[19]
Adverse effects
[edit]The most common adverse 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.[20]
Interactions
[edit]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.[20]
Functions
[edit]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.[21] It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.[7]
Cofactor for tryptophan hydroxylases
[edit]Tetrahydrobiopterin is a cofactor for tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP).
Cofactor for phenylalanine hydroxylase
[edit]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
[edit]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;[22] currently, this condition is typically treated with carbidopa/levodopa, which directly restores dopamine levels within the brain.
Cofactor for nitric oxide synthase
[edit]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.[23] As a co-factor for nitric oxide synthase, tetrahydrobiopterin supplementation has shown beneficial results for the treatment of endothelial dysfunction in animal experiments and clinical trials, although the tendency of BH4 to become oxidized to BH2 remains a problem.[24]
Cofactor for ether lipid oxidase
[edit]Ether lipid oxidase (alkylglycerol monooxygenase, AGMO) catalyses the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol.
History
[edit]Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase (PAH).[25]
Biosynthesis and recycling
[edit]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).[26]
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,[27] 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.[28] 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.[29]
Research
[edit]Other than PKU studies, tetrahydrobiopterin has participated in clinical trials studying other approaches to solving conditions resultant from a deficiency of tetrahydrobiopterin. These include autism, depression,[30] ADHD, hypertension, endothelial dysfunction, and chronic kidney disease.[31][32] Experimental studies suggest that tetrahydrobiopterin regulates deficient production of nitric oxide in cardiovascular disease states, and contributes to the response to inflammation and injury, for example in pain due to nerve injury. A 2015 BioMarin-funded study of PKU patients found that those who responded to tetrahydrobiopterin also showed a reduction of ADHD symptoms.[33]
Depression
[edit]In psychiatry, tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression, although evidence is inconclusive to date.[34]
Autism
[edit]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.[35] 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."[36]
Cardiovascular disease
[edit]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.[37] Increasing tetrahydrobiopterin in endothelial cells by augmenting the levels of the biosynthetic enzyme GTPCH can maintain endothelial nitric oxide synthase function in experimental models of disease states such as diabetes,[38] atherosclerosis, and hypoxic pulmonary hypertension.[39] However, treatment of people with existing coronary artery disease with oral tetrahydrobiopterin is limited by oxidation of tetrahydrobiopterin to the inactive form, dihydrobiopterin, with little benefit on vascular function.[40]
Neuroprotection in prenatal hypoxia
[edit]Depletion of tetrahydrobiopterin occurs in the hypoxic brain and leads to toxin production. Preclinical studies in mice reveal that treatment with oral tetrahydrobiopterin therapy mitigates the toxic effects of hypoxia on the developing brain, specifically improving white matter development in hypoxic animals.[41]
Programmed cell death
[edit]GTPCH (GCH1) and tetrahydrobiopterin were found to have a secondary role protecting against cell death by ferroptosis in cellular models by limiting the formation of toxic lipid peroxides.[42] Tetrahydrobiopterin acts as a potent, diffusable antioxidant that resists oxidative stress[43] and enables cancer cell survival via promotion of angiogenesis.[44]
References
[edit]- ^ "Sapropterin (Kuvan) Use During Pregnancy". Drugs.com. 17 May 2019. Retrieved 4 March 2020.
- ^ a b "Kuvan Product information". Health Canada. 25 April 2012. Retrieved 24 June 2022.
- ^ a b c "Kuvan- sapropterin dihydrochloride tablet Kuvan- sapropterin dihydrochloride powder, for solution Kuvan- sapropterin dihydrochloride powder, for solution". DailyMed. 13 December 2019. Retrieved 4 March 2020.
- ^ a b c d "Kuvan EPAR". European Medicines Agency (EMA). 4 March 2020. Retrieved 4 March 2020.
- ^ "Sapropterin". Drugs.com. 28 February 2020. Retrieved 4 March 2020.
- ^ "International Non-proprietary Names for Pharmaceutical Substances (INN)". Fimea. Retrieved 4 March 2020.
- ^ a b Kappock TJ, Caradonna JP (November 1996). "Pterin-Dependent Amino Acid Hydroxylases". Chemical Reviews. 96 (7): 2659–2756. doi:10.1021/CR9402034. PMID 11848840.
- ^ Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis Progress in Neuro-Psychopharmacology and Biological Psychiatry 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633
- ^ 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.
- ^ Bhagavan NV (2015). Essentials of Medical Biochemistry With Clinical Cases, 2nd Edition. USA: Elsevier. p. 256. ISBN 978-0-12-416687-5.
- ^ 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.
- ^ "Drug Approval Package: Kuvan (Sapropterin Dihydrochloride) NDA #022181". U.S. Food and Drug Administration (FDA). 24 March 2008. Retrieved 4 March 2020.
- Lay summary in: Daniel A. Shames (13 December 2007). "Summary Review: Application number: 22-181" (PDF). U.S. Food and Drug Administration.
- ^ a b c d "Kuvan (sapropterin dihydrochloride) Tablets and Powder for Oral Solution for PKU". BioMarin. Retrieved 4 March 2020.
- ^ "Drug Approval Package: Kuvan Powder for Oral Solution (Sapropterin Dihydrochloride) NDA #205065". U.S. Food and Drug Administration (FDA). 28 February 2014. Retrieved 4 March 2020.
- ^ Herper M (28 July 2016). "How Focusing On Obscure Diseases Made BioMarin A $15 Billion Company". Forbes. Retrieved 9 October 2017.
- ^ "BioMarin Announces Kuvan (sapropterin dihydrochloride) Patent Challenge Settlement". BioMarin Pharmaceutical Inc. 13 April 2017. Retrieved 9 October 2017 – via PR Newswire.
- ^ "Tetrahydrobiopterin Deficiency". National Organization for Rare Disorders (NORD). Retrieved 9 October 2017.
- ^ "What are common treatments for phenylketonuria (PKU)?". NICHD. 23 August 2013. 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.
- ^ a b Haberfeld, H, ed. (1 March 2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Kuvan 100 mg-Tabletten.
- ^ Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis Progress in Neuro-Psychopharmacology and Biological Psychiatry 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633
- ^ "Genetics Home Reference: GCH1". National Institutes of Health.
- ^ 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.
- ^ Yuyun MF, Ng LL, Ng GA (2018). "Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy?". Microvascular Research. 119: 7–12. doi:10.1016/j.mvr.2018.03.012. PMID 29596860.
- ^ Kaufman S (February 1958). "A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine" (PDF). The Journal of Biological Chemistry. 230 (2): 931–9. doi:10.1016/S0021-9258(18)70516-4. PMID 13525410.
- ^ 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.
- ^ Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis Progress in Neuro-Psychopharmacology and Biological Psychiatry 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633
- ^ "Search results for Kuvan". ClinicalTrials.gov. U.S. National Library of Medicine.
- ^ "BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric Symptoms in Subjects with PKU". BioMarin Pharmaceutical Inc. 17 August 2010.
- ^ Burton B, Grant M, Feigenbaum A, Singh R, Hendren R, Siriwardena K, et al. (March 2015). "A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria". Molecular Genetics and Metabolism. 114 (3): 415–24. doi:10.1016/j.ymgme.2014.11.011. PMID 25533024.
- ^ Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis Progress in Neuro-Psychopharmacology and Biological Psychiatry 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633
- ^ 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.
- ^ Alp NJ, Mussa S, Khoo J, Cai S, Guzik T, Jefferson A, et al. (September 2003). "Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression". The Journal of Clinical Investigation. 112 (5): 725–35. doi:10.1172/JCI17786. PMC 182196. PMID 12952921.
- ^ Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, et al. (April 2005). "Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension". Circulation. 111 (16): 2126–33. doi:10.1161/01.CIR.0000162470.26840.89. PMID 15824200.
- ^ Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, et al. (March 2012). "Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease". Circulation. 125 (11): 1356–66. doi:10.1161/CIRCULATIONAHA.111.038919. PMC 5238935. PMID 22315282.
- ^ Romanowicz J, Leonetti C, Dhari Z, Korotcova L, Ramachandra SD, Saric N, et al. (August 2019). "Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease". Journal of the American Heart Association. 8 (15): e012711. doi:10.1161/JAHA.119.012711. PMC 6761654. PMID 31331224.
- ^ Kraft VA, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, et al. (January 2020). "GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling". ACS Central Science. 6 (1): 41–53. doi:10.1021/acscentsci.9b01063. PMC 6978838. PMID 31989025.
- ^ Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F, et al. (December 2020). "Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers". Nature Chemical Biology. 16 (12): 1351–1360. doi:10.1038/s41589-020-0613-y. PMC 8299533. PMID 32778843.
- ^ Chen L, Zeng X, Wang J, Briggs SS, O'Neill E, Li J, et al. (November 2010). "Roles of tetrahydrobiopterin in promoting tumor angiogenesis". The American Journal of Pathology. 177 (5): 2671–2680. doi:10.2353/ajpath.2010.100025. PMC 2966821. PMID 20847284.
Further reading
[edit]- "Clinical Review Report: Sapropterin dihydrochloride (Kuvan)". CADTH Common Drug Reviews. Ottawa, Canada: Canadian Agency for Drugs and Technologies in Health (CADTH). September 2017. PMID 30462435. Bookshelf ID: NBK533813.
- 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. hdl:11336/126862. 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.
External links
[edit]- "Sapropterin". Drug Information Portal. U.S. National Library of Medicine.
- "Sapropterin dihydrochloride". Drug Information Portal. U.S. National Library of Medicine.