Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration

• Published in: Molecular genetics and metabolism 2004, Vol.81 (1), p.45-51
• Main Authors: Fiege, Betina, Ballhausen, Diana, Kierat, Lucja, Leimbacher, Walter, Goriounov, Dimitri, Schircks, Bernhard, Thöny, Beat, Blau, Nenad
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Biopterin; Biopterins - administration & dosage; Biopterins - analogs & derivatives; Biopterins - blood; Biopterins - pharmacokinetics; Body Weight; dithioerythritol; Dithioerythritol - blood; Dithioerythritol - metabolism; Dose-Response Relationship, Drug; Endothelial dysfunction; Enzyme Stability; Humans; Hydrogen-Ion Concentration; Hyperphenylalaninemia; Male; Middle Aged; Models, Biological; NOS; Oxidation-Reduction; phenylalanine hydroxylase; PKU; tetrahydrobiopterin; Time Factors
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2003.09.014

Tetrahydrobiopterin (BH 4) is widely used as a therapeutic agent in patients with BH 4 deficiencies and mild forms of phenylketonuria (PKU) and there is an increasing need for the measurement of its plasma concentrations in patients with cardiovascular disorders. We measured BH 4 and total biopterin in dithioerythritol (DTE) pretreated plasma from four adults after oral administration of BH 4 (2, 10, and 20 mg/kg body weight) using the differential iodine oxidation method. About 80% (range 64.8–92.2% ) of total biopterin was found as BH 4 when analyzed immediately after blood sampling. Compared with ascorbic acid as an antioxidant, DTE was more protective against oxidation of BH 4, particularly in samples stored over a period of 8 months. Without antioxidant (DTE or ascorbic acid) almost no BH 4 was detected. Furthermore, BH 4 and total biopterin were measured at different time intervals (up to 33 h after oral administration) and pharmacokinetic parameters T max (1–4 h), C max (258.7–259.0 nmol/L biopterin at a dosage of 10 mg/kg), and area under the curve (AUC=1708–1958 nmol *h/L up to T=10 h) were estimated. The elimination half-life time was calculated to be 3.3–5.1 h. Doubling the BH 4 dosage to 20 mg/kg resulted in 60% higher AUC while sublingual BH 4 application (2 mg/kg) resulted in 58–76% higher BH 4 plasma concentrations when compared with oral administration. These preliminary data suggest that in patients with BH 4 cofactor defects and BH 4-responsive phenylalanine hydroxylase deficiency, BH 4 should be given in at least two to three daily doses and that sublingual administration may lower the required BH 4 dosage and subsequently the cost of treatment. Due to inter individual differences in pharmacokinetic properties, in some patients with hyperphenylalaninemia and mild PKU plasma BH 4 levels may be not high enough to fully activate the liver phenylalanine hydroxylase and thus lower blood phenylalanine levels. Assessment of plasma BH 4 or total biopterin concentrations may be a good way to control the efficacy of the loading test.