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Trade namesKuvan, Biopten, other
Other namesTetrahydrobiopterin, Sapropterin hydrochloride (JAN JP), Sapropterin dihydrochloride (USAN US)
  • (6R)-2-Amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridin-4(1H)-one
Clinical data
Main usesPhenylketonuria, tetrahydrobiopterin deficiency[1][2]
Side effectsHeadache, runny nose, anaphylaxis, stomach inflammation, hyperactivity[1][2]
  • AU: B1[3]
  • US: C (Risk not ruled out)[3]
Routes of
By mouth
Duration of action24 hours[1]
Typical dose5-20 mg/kg per day[4]
External links
License data
Legal status
Elimination half-life4 hours (healthy adults)
6–7 hours (PKU patients)
Chemical and physical data
Molar mass241.251 g·mol−1
3D model (JSmol)
  • CC(C(C1CNC2=C(N1)C(=O)N=C(N2)N)O)O
  • InChI=1S/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1 checkY

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 before and during sapropterin supplementation a,b) FDG-PET regions of interest c,d) normal brain e,f) participants before g,h) and after supplementation ( 126 days)

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]


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]


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]


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]


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]



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]


  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 "Sapropterin Monograph for Professionals". Archived from the original on 29 August 2021. Retrieved 10 October 2021.
  2. 2.0 2.1 2.2 2.3 2.4 "Kuvan". Archived from the original on 14 August 2020. Retrieved 10 October 2021.
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  4. 4.0 4.1 4.2 "Sapropterin dihydrochloride (Kuvan)" (PDF). CADTH. September 2017. Archived (PDF) from the original on 11 February 2020. Retrieved 10 October 2021.
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  19. Bhagavan, N. V. (2015). Essentials of Medical Biochemistry With Clinical Cases, 2nd Edition. USA: Elsevier. p. 256. ISBN 978-0-12-416687-5.
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External links