Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration

Tetrahydrobiopterin (BH4) is widely used as a therapeutic agent in patients with BH4 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 BH4 and total biopterin in dithioerythritol (DTE) pretreated plasma from four adults after oral administration of BH4 (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 BH4 when analyzed immediately after blood sampling. Compared with ascorbic acid as an antioxidant, DTE was more protective against oxidation of BH4, particularly in samples stored over a period of 8 months. Without antioxidant (DTE or ascorbic acid) almost no BH4 was detected. Furthermore, BH4 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 BH4 dosage to 20 mg/kg resulted in 60% higher AUC while sublingual BH4 application (2 mg/kg) resulted in 58-76% higher BH4 plasma concentrations when compared with oral administration. These preliminary data suggest that in patients with BH4 cofactor defects and BH4-responsive phenylalanine hydroxylase deficiency, BH4 should be given in at least two to three daily doses and that sublingual administration may lower the required BH4 dosage and subsequently the cost of treatment. Due to inter individual differences in pharmacokinetic properties, in some patients with hyperphenylalaninemia and mild PKU plasma BH4 levels may be not high enough to fully activate the liver phenylalanine hydroxylase and thus lower blood phenylalanine levels. Assessment of plasma BH4 or total biopterin concentrations may be a good way to control the efficacy of the loading test. (C) 2003 Elsevier Inc. All rights reserved.