Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
Saproterenol is the synthetic form of the naturally occurring enzyme cofactor tetrahydrobiopterin (BH4) used to treat phenylketonuria (PKU). BH4 is present in normal human milk and is a cofactor in many responses, including acting as a catalyst for phenylalanine hydroxylase. In two post-marketing pregnancy registry studies of saproterenol, 16 women taking saproterenol were identified as lactating, with a mean lactation period of 3.5 months. No breastfeeding-related safety issues were reported in infants of mothers taking saproterenol. Guidelines in the United States and Europe state that saproterenol hydrochloride supplementation as an adjunct to dietary therapy is not contraindicated for lactating women who respond to BH4.
◉ Effects on Breastfed Infants
A Japanese woman with PKU took 500 mg (10 mg/kg) of saproterenol hydrochloride daily during pregnancy and postpartum. She breastfed the infant (feeding duration not specified) until the infant was 25 months old. The infant's developmental milestones were normal at 31 months of age, and growth and development were normal.
◉ Impact on lactation and breast milk
As of the revision date, no relevant published information was found.

Mol Genet Metab. 2016 Jan;117(1):5-11.

Sapropterin is a tetrahydropterin, chemically named 2-amino-5,6,7,8-tetrahydropterin-4(3H)-one, in which the hydrogen at the 6-position is replaced by a 1,2-dihydroxypropyl group (6R,1'R,2'S-enantiomer). It functions as a coenzyme, diagnostic reagent, human metabolite, and cofactor. Sapropterin (tetrahydrobiopterin or BH4) is a cofactor in the synthesis of nitric oxide. It is also crucial for the conversion of phenylalanine to tyrosine catalyzed by phenylalanine-4-hydroxylase, and for the conversion of tyrosine to L-DOPA catalyzed by tyrosine hydroxylase. Tryptophan hydroxylase catalyzes the conversion of tryptophan to 5-hydroxytryptophan. L-Erythro-tetrahydrobiopterin is a metabolite found in or produced by Escherichia coli (K12 strain, MG1655 strain). Sapropterin is a phenylalanine hydroxylase activator. The mechanism of action of sapropterin is as a phenylalanine hydroxylase activator, a breast cancer resistance protein inhibitor, and a P-glycoprotein inhibitor. Tetrahydrobiopterin is an essential cofactor for the activity of aromatic amino acid hydroxylases. Tetrahydrobiopterin degrades phenylalanine and promotes the biosynthesis of various neurotransmitters and the production of nitric oxide. See also: sapropterin dihydrochloride (salt form). Sapropterin hydrochloride (active ingredient). Drug Indications For the treatment of tetrahydrobiopterin (BH4) deficiency. Sapropterin (Dipharma) is indicated for the treatment of hyperphenylalaninemia (HPA) in adults and patients of all ages with phenylketonuria (PKU) who have responded to treatment. Sapropterin (Dipharma) is also indicated for the treatment of hyperphenylalaninemia (HPA) in adults and patients of all ages with tetrahydrobiopterin (BH4) deficiency who have responded to treatment. Kuvan is indicated for the treatment of hyperphenylalaninemia (HPA) in adults and children of all ages with phenylketonuria (PKU) who have responded to treatment. Kuvan is also indicated for the treatment of hyperphenylalaninemia (HPA) in adults and children of all ages with tetrahydrobiopterin (BH4) deficiency, and has been shown to be effective in this treatment. Mechanism of Action: Tetrahydrobiopterin (BH4) is a natural cofactor or coenzyme of phenylalanine-4-hydroxylase (PAH), tetrahydrobiopterin, and tryptophan-5-hydroxylase. Tetrahydrobiopterin is also a natural cofactor of nitric oxide synthase. Therefore, BH4 is essential for the conversion of phenylalanine to tyrosine, adrenaline production, and the synthesis of monoamine neurotransmitters (serotonin, dopamine, and norepinephrine). It is also involved in apoptosis and other cellular events mediated by nitric oxide production. As a coenzyme, BH4 reacts with molecular oxygen to generate reactive oxygen species (ROS) intermediates, which can hydroxylate substrates. During hydroxylation, the coenzyme loses two electrons and is regenerated in vivo through a NADH-dependent reaction. As a cofactor of PAHs, tetrahydrobiopterin promotes the conversion of phenylalanine to tyrosine and reduces the concentration of phenylalanine in the blood, thereby mitigating the toxic effects of this amino acid. Normal serum phenylalanine concentration is 100 μmol, while elevated (toxic) concentrations are typically >1200 μmol. Individuals deficient in tetrahydrobiopterin cannot effectively convert phenylalanine to tyrosine. Supplementation with tetrahydrobiopterin can enhance enzyme activity. As a cofactor of tyrosine hydroxylase, BH4 promotes the conversion of tyrosine to levodopa; as a cofactor of tryptophan hydroxylase, BH4 promotes the conversion of tryptophan to 5-hydroxytryptophan, which is further converted to serotonin.

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Pharmacodynamics
Tetrahydrobiopterin (BH4) is used to convert various amino acids, including phenylalanine, into other essential molecules in the body, such as neurotransmitters. Tetrahydrobiopterin deficiency can be caused by mutations in the genes for GTP cyclase 1 (GCH1), 6-pyruvyltetrahydropterin synthase/hepatocyte nuclear factor 1α dimerization cofactor (PCBD1), 6-pyruvyltetrahydropterin synthase (PTS), and quinone dihydropteridine reductase (QDPR). These genes encode enzymes that are crucial for the production and cycling of tetrahydrobiopterin. If one of these enzymes malfunctions due to a gene mutation, the production of tetrahydrobiopterin will be low or nonexistent. As a result, dietary phenylalanine accumulates in the blood and other tissues and can damage nerve cells in the brain. High levels of phenylalanine can lead to a range of signs and symptoms, including transient hypotonia, intellectual disability, motor disorders, dysphagia, seizures, behavioral problems, progressive developmental disorders, and thermoregulation disorders.

C9H15N5O3

241.2471

241.117

62989-33-7

Tetrahydrobiopterin;17528-72-2;Sapropterin dihydrochloride;69056-38-8

135398654

Typically exists as solid at room temperature

1.9±0.1 g/cm3

506.6±60.0 °C at 760 mmHg

250-255 °C (hydrochloride salt)
250 - 255 °C (hydrochloride salt)

260.2±32.9 °C

0.0±3.0 mmHg at 25°C

1.822

-4.22

6

6

2

17

405

3

C[C@@H]([C@@H]([C@H]1CNC2NC(=NC(=O)C=2N1)N)O)O

FNKQXYHWGSIFBK-RPDRRWSUSA-N

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

(6R)-2-Amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridin-4(1H)-one

Tetrahydro-6-biopterin; Dapropterin; Phenoptin; THB; BPH4; 6R-BH4; Tetrahydrobiopterin, sapropterin; trade name Kuvan.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)